The invention is directed to steroid compounds and in particular to 6,7-oxygenated steroid compounds and therapeutic uses related thereto.
Asthma and allergy are closely related with good evidence from clinical studies demonstrating a strong correlation between the severity of asthma and the degree of atopy (allergy). Sensitization to allergens is believed to be the most important risk factor for asthma in both children and adults, with approximately 90% of asthma cases exhibiting atopy.
Allergy is characterized by an increased blood serum IgE (antibody) level. Repeated exposure to allergens, in a process called sensitization, is normally required to elicit sufficient B cell production of IgE specific to a given allergen or series of allergens to trigger atopy and the subsequent asthmatic or allergic response. Once B cells are exposed to allergens they produce antibodies which bind to the surface of mast cells. The crosslinking of 2 antibodies by the antigen causes a series of reactions causing degranulation and the release of a number of mediators which modulate the inflammatory response. Mediators that are released or generated during the asthmatic and allergic response include histamine, leukotrienes, prostaglandins, cytokines and tryptase.
Asthma is characterized by hyperresponsiveness of the airways, episodic periods of bronchospasm and chronic inflammation of the lungs. Obstruction of the airways is reversible with time or in response to drug therapies. Patients exhibiting normal airflow may be hyperreactive to a variety of naturally occurring stimuli, e.g., cold air, exercise, chemicals and allergen. The most common event initiating an asthmatic response is an immediate hypersensitivity to common allergens including ragweed pollen, grass pollen, various fungi, dust mites, cockroaches and domestic animals. The symptoms of the disease include chest tightness, wheezing, shortness of breath and coughing. Mild forms of the disease occur in up to 10% of the U.S. population, while the U.K., Australia and New Zealand report higher prevalences. Asthma incidence and mortality has been increasing worldwide, doubling over the past 20 years despite modern therapies.
The response of the airways to allergen is complex and consists of an early asthmatic response (EAR) which peaks 20-30 min after exposure to the stimuli, is characterized by bronchoconstriction and normally resolves after 1xc2xd to 2 hours. The late asthmatic response (LAR) generally occurs 3-8 hours after initial exposure, and involves both bronchoconstriction and the development of inflammation and edema in the lung tissue. This inflammation often becomes chronic, with epithelial damage occurring and infiltration of the lungs with inflammatory cells such as eosinophils and neutrophils.
Glucocorticosteroids (steroids) are the most effective long-term therapy for the treatment of asthma. Oral steroids are not very useful for the control of acute asthma attacks and their chronic use in the control of asthma is minimal due to the introduction of inhaled steroids. Due to the presence of airway inflammation even in mild asthma, inhaled steroids are used even in early stage drug therapy. As effective as inhaled steroids are, side effects limit their use and combination therapy is often employed. Combination therapy is divided into the following areas: anti-inflammatory drugs (e.g., inhaled and oral steroids), bronchodilators, (e.g., xcex22-agonists, xanthines, anticholinergics), and mediator inhibitors (e.g., cromolyns and leukotriene antagonists).
Cromolyns (e.g., disodium cromoglycate and nedocromil) inhibit the release of histamine in vitro and prevent bronchial hyperreactivity, while displaying few side effects. They are not effective orally and have no bronchodilator effect. Usually chronic treatment (several days) is required to achieve optimal anti-inflammatory effect, though cromolyns exhibit beneficial effects against exercise-induced asthma when administered only 10 minutes prior to exercise. Cromolyns are, at best, only marginally effective against moderate to severe asthma.
Glucocorticosteroids (steroids) have profound effects against lung inflammation, and are by far the most effective drugs for the treatment of asthma and allergies. In mast cells they inhibit the production of arachidonic acid metabolites (leukotrienes and prostaglandins) and cytokines. Responses to inhaled steroids or systemic steroids can occur within 4 hours but may take several days depending on the severity of the disease state. Symptoms often return without regular chronic treatment. Side effects of inhaled steroids used on a continual basis include dysphonia, local irritation and oral candidiasis (a fungal infection). Higher doses of inhaled steroids cause suppression of the HPA-axis which is responsible for the regulation of serum cortisol levels, metabolism, stress, CNS function and immunity. Continuous use of high dose inhaled steroids or oral steroids induce more severe side effects: severe suppression of the HPA axis, causing effects on the immune system, hypertension, osteoporosis, peptic ulcers, growth retardation in children, behavioral problems, reproductive problems, cataracts and hematological disorders.
Beta-agonists reverse the bronchospasm produced during an asthmatic attack and have a modest activity against the onset of the response. Their routes of administration and duration of action are variable. Prolonged use of these agents can cause decreased response to the therapy itself with the development of tolerance. These compounds have no effect on the inflammatory response itself.
Xanthines, which are cyclic AMP phosphodiesterase inhibitors, are also used in bronchodilator therapy. Though effective, xanthine activity is influenced by a number of factors including food, age, smoking, etc. The therapeutic window is relatively narrow and side effects include gastrointestinal disorders, CNS disturbances, headache, anxiety and cardiac arrhythmias. The importance of treatment of inflammation in asthma and allergy has led to a decline in the use of xanthines for therapy.
Anticholinergic agents such as ipratropium bromide are used to block the contraction of bronchial smooth muscle induced by acetylcholine released as a neurotransmitter. Some positive effects are reported in asthma, with these drugs being most effective against chronic obstructive pulmonary disease. A large number of side effects are seen with these drugs including urinary retention, dry mouth, tachycardia, nausea, vomiting, flushing and hypertension.
Inhibitors of 5-lipoxygenase inhibit the generation of leukotrienes, while leukotriene antagonists prevent the action of leukotrienes, which are potent bronchospastic mediators released during an asthmatic reaction. Use of leukotriene synthesis inhibitors has been associated with increased liver enzymes, indicating the need to monitor liver function closely in certain patient populations. Leukotriene inhibitors have shown comparative activity to the cromolyns, and activity equivalent to low dose corticosteroids.
In general, moderate to severe asthma patients are poorly served by the present armamentarium of drugs. Drugs that are safe are only marginally effective, while effective drugs have unacceptable side effects with extensive monitoring of patients required. There is a significant need for therapeutic agents that achieve safe and effective relief of asthma and allergy symptoms. The present invention provides these and related benefits as described herein.
One aspect of the invention provides compounds of the formula: 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O,xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C17 is substituted according to any of (c), (d), (e), (f), (g), (h) and (i):
(c) xe2x95x90C(R2)(R3) except when C14 is substituted with methyl;
(d) xe2x80x94R5 and xe2x80x94OR6 so long as the A and B rings are not aromatic, and when C10 is substituted with methyl then C5 is not bonded directly to oxygen, where R5 and R6 may together form a direct bond so C17 is a carbonyl group, or may together with C17 form a cyclic 3-6 membered ether or 4-6 membered lactone; otherwise R5 is R4 or xe2x80x94OR6 and R6 is R1 or R4;
(e) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6, as long as one of the following conditions i), ii), iii) or iv) apply:
i) C5 is substituted with a hydrogen in the alpha configuation, and C3 is not bonded to oxygen, and when C3 is substituted with two hydrogen atoms then C17 is not substituted with either xe2x80x94CH(CH3)(CH2)3CH(CH3)2 or xe2x80x94CH(CH3)(CH2)2C(xe2x95x90O)OCH3;
ii) C10 and C13 are not simultaneously substituted with methyl, and when C10 is substituted with methyl, then C14 is not substituted with a methyl, and the A ring is never aromatic;
iii) if C3 and C4 are bonded to oxygen atoms, and the C6-OR1 substituent has the alpha configuration, and the C7-OR1 substituent has the beta configuration, then C17 is not substituted with any of the following: 
iv) C3 and C4 are each bonded to the same oxygen atom so as to form an oxirane ring, with the proviso that C7 does not have carbonyl substitution when C5 has hydroxyl or xe2x80x94OR1 substitution;
(f) two of the following substituents, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, as long as one of the above conditions i), ii), iii) or iv) apply;
(g) a cyclic structure of the formula 
xe2x80x83wherein G is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OR1)xe2x80x94, xe2x80x94C(R4)(OR1)xe2x80x94 or xe2x80x94C(OR1)(OR1)xe2x80x94, as long as C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl;
(h) two hydrogen atoms, as long as C3 is not substituted with a carbonyl group;
(i) one hydrogen atom and one group selected from C1-C30 hydrocarbyl groups and C1-C30 halogen substituted hydrocarbyl groups, excluding xe2x80x94CH(CH3)(CH2)3CH(CH3)2;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R2, R3 and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In a preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10 and C13 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C14 is substituted with xe2x80x94X, xe2x80x94OR1, or xe2x80x94R4 excluding methyl;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R2, R3 and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated, with the proviso that neither the A nor B ring is aromatic;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
R5 and R6 may together form a direct bond so C17 is a carbonyl group, or may together with C17 form a cyclic 3-6 membered ether or 4-6 membered lactone; otherwise R5 is R4 or xe2x80x94OR6 and R6 is R1 or R4; and
X represents fluoride, chloride, bromide and iodide;
with the proviso that when C10 is substituted with methyl, then C5 is not directly bonded to an oxygen atom.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C3 is substituted with one of xe2x95x90C(R4)(R4) and xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 wherein n ranges from 1 to about 6, or two of xe2x80x94X, and xe2x80x94R4 with the proviso that C3 is not bonded to an oxygen atom, and when C3 is substituted with two hydrogen atoms then C17 is not substituted with either xe2x80x94CH(CH3)(CH2)3CH(CH3)2 or xe2x80x94CH(CH3)(CH2)2C(xe2x95x90O)OCH3;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represent a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
with the provisos that (a) C10 and C13 are not simultaneously substituted with methyl, and (b) when C10 is substituted with methyl, then C14 is not substituted with a methyl;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated with the proviso that the A ring is not aromatic;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represent a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
with the proviso that C17 is not substituted with any of the following: 
each of C5, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C8 is substituted with xe2x80x94X or xe2x80x94R4 and is preferably not bonded directly to oxygen;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected; xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
with the proviso that C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl, and are preferably not simultaneously substituted with oxygen atoms;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
G is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OR1)xe2x80x94, xe2x80x94C(R4)(OR1)xe2x80x94 or xe2x80x94C(OR1)(OR1)xe2x80x94;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;.
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another preferred embodiment, the compounds have the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide;
with the proviso that C7 does not have carbonyl substitution when C5 has hydroxyl or xe2x80x94OR1 substitution.
In another preferred embodiment, the compounds have one of the formulas 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12 and C16 is independently substituted according to (a) or (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6,
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
C5 is substituted with a hydrogen atom;
each of C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1; and
C17 is substituted according to (c), (d), (e) or (f):
(c) two substituents selected from hydrogen, halogen, C1-C30 saturated hydrocarbyl excluding xe2x80x94CH(CH3)(CH2)3CH(CH3)2, halogen substituted C1-C30 saturated hydrocarbyl, C1-C30 unsaturated hydrocarbyl, and halogen substituted C1-C30 unsaturated hydrocarbyl;
(d) one substituent selected from xe2x95x90C(R4)(R4) with the proviso that C14 is not substituted with methyl;
(e) at least one oxygen atom-containing substituent selected from xe2x95x90O, xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6, xe2x80x94OH, and xe2x80x94OR1;
(f) at least one nitrogen atom-containing substituent selected from xe2x80x94N(R4)(R4) wherein the two R4 groups may together with the nitrogen atom form one or more rings, so that the nitrogen atom-containing substituent includes nitrogen atom-containing heterocyclic groups; wherein
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where xe2x80x94OR1 groups bonded to adjacent carbon atoms may together form a cyclic structure which protects both hydroxyl groups;
R4 at each occurrence is independently selected from H and R5;
R5 is a C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R5 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide or iodide.
In another aspect, the invention provides a pharmaceutical composition comprising a compound according any of the descriptions provided above, in combination with a pharmaceutically acceptable carrier or diluent.
In another aspect, the invention provides a pharmaceutical composition comprising a compound in combination with a pharmaceutically acceptable carrier or diluent, the compound having the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted with a substituent selected from (a) or (b), wherein
(a) represents one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94, wherein n ranges from 1 to about 6; and
(b) represents two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, which are independently selected at each occurrence;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where the C6 and C7-OR1 groups may together form a cyclic structure which protects both hydroxyl groups;
R4 at each occurrence is independently selected from H and R5;
R5 is a C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide or iodide;
with the proviso that C15 is not bonded to an oxygen atom.
In another aspect, the invention provides for the use of the above compounds (any one or mixture thereof) for manufacture of a medicament for the treatment of asthma, allergy, inflammation including arthritis, and/or thrombosis, or for treating a condition associated with an elevated level of NFxcexaB.
In another aspect, the invention provides a process for treating asthma comprising administering to a subject in need thereof an effective amount of the compound or salt thereof, or a pharmaceutical composition, each as described above.
In another aspect, the invention provides a process for treating allergy comprising administering to a subject in need thereof an effective amount of the compound or salt thereof, or a pharmaceutical composition, each as described above.
In another aspect, the invention provides a process for treating inflammation due to arthritis comprising administering to a subject in need thereof an effective amount of the compound or salt thereof, or a pharmaceutical composition, each as described above.
In another aspect, the invention provides a process for treating thrombosis comprising administering to a subject in need thereof an effective amount of the compound or salt thereof, or a pharmaceutical composition, each as described above.
In another aspect, the invention provides a process for treating a condition associated with an elevated level of NFxcexaB activity in a subject, comprising administering to a subject in need thereof an effective amount of the compound or salt thereof, or a pharmaceutical composition, each as described above.
In another aspect, the invention provides a process for introducing an exocyclic olefin group to the C17 position of a 6,7-dioxygenated steroid comprising providing a compound of Formula (10), reacting the compound of Formula (10) with a Wittig reagent of Formula (11) in the presence of a base, to provide an olefin compound of Formula (12) 
wherein each of the compounds of Formulas (10) and (12) include pharmaceutically acceptable salts and solvates thereof, and wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
Ra, Rb and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide, which is independently selected at each occurrence.
In another aspect, the invention provides a process for introducing 6xcex1,7xcex2-dioxygenation into a steroid, comprising providing a steroid of Formula (13) having a carbonyl group at C7 and a double bond between C5 and C6, comprising a reduction the carbonyl group to a hydroxyl group, followed by a hydroboration of the double bond to provide a hydroxyl group at C6, wherein the C6 hydroxyl group has the xcex1-configuration and the C7 hydroxyl group has the xcex2-configuration, 
wherein each of the compounds of Formulas (13) and (14) include pharmaceutically acceptable salts and solvates thereof, and wherein:
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In another aspect, the invention provides a process for a stereocontrolled introduction of a hydroxyl group at C3 of a steroid nucleus, comprising providing a steroid compound of Formula (15) having a carbonyl group at C3, and reducing the carbonyl group to a hydroxyl group with a reducing agent so as to provide at least one compound of Formulas (16) and (17) 
wherein each of the compounds of Formulas (15), (16) and (17) include pharmaceutically acceptable salts and solvates thereof, and wherein:
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
The invention is directed to various steroid derivatives having specific functionality as described in detail herein. The compounds described herein demonstrate effectiveness as good controllers of the asthmatic and allergic responses in that they show efficacy against mast cell degranulation, inhibition of allergen-induced bronchospasm (acute phase) and inhibition of allergen-induced lung inflammation (late phase). This group of compounds represents a new series of agents which have potential therapeutic benefit in the treatment of asthma and allergies, with high potency, a broad spectrum of activity and the reduced probability of side effects.
For convenience in identifying the novel features of the invented compounds, an unsubstituted steroid nucleus having each ring carbon thereof identified with a unique number is shown below as Structure 1. This numbering system will be used consistently herein. 
The compounds of the present invention contain at least two asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the compounds of the above formula. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the above formulae are included within the present invention.
The synthesis procedures described herein, especially when taken with the general knowledge in the art, provide sufficient guidance to those of ordinary skill in the art to perform the synthesis, isolation, and purification of the preferred compounds described herein and other analogous compounds. Individual enantiomers may be obtained, if desired, from mixtures of the different forms by known methods of resolution, such as the formation of diastereomers, followed by recrystallization.
The compounds of the above formula may be in the form of a solvate or a pharmaceutically acceptable salt, e.g., an acid addition salt. Such salts include hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art.
A compound of the present invention may be prepared as a composition by combining it with a pharmaceutically acceptable carrier or diluent. Suitable carriers or diluents include physiological saline. It will be evident to those of ordinary skill in the art that a composition of the present invention may contain more than one steroid compound or one or more steroid compounds in combination with one or more non-steroid compounds.
A specific functionality present on many of the steroid compounds of the invention is oxygen substitution at both of positions 6 and 7. Thus, certain steroids of the invention have the oxygen substitution pattern shown in Structure 2 below. Some of these steroids are additionally characterized by having specific stereochemistries. For example, steroids having 6xcex1 and 7xcex2 oxygen substitution, as shown in Structure 3, and steroids having an alpha hydrogen at the 5 position in addition to having 6xcex1 and 7xcex2 oxygen substitution, as shown in Structure 4 below, fall within the scope of the invention. 
In Structures 2, 3 and 4, each of the oxygen atoms that are bonded to carbons 6 and 7 are simultaneously bonded to an xe2x80x9cR1xe2x80x9d group. The R1 group is hydrogen or a protecting group for an hydroxyl group. Suitable protecting groups are set forth in Greene, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, New York N.Y. (1981). When a compound of Structures 2-4 contains vicinal xe2x80x94OR1 groups (i.e., xe2x80x94OR1 groups on neighboring carbon atoms), those vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups. A ketal is an example of protected vicinal xe2x80x94OR1 group. Geminal xe2x80x94OR1 groups (i.e., two xe2x80x94OR1 groups on the same carbon atom) may together form a cyclic structure which protects a carbonyl group. A ketal is an example of such a cyclic structure. It should be understood that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group, and thus at C6 and C7, R1 may be a direct bond between the oxygen atom and the carbon (C6 or C7) to which the oxygen atom is bonded.
Steroids of the invention may have substituents with either the a or stereochemistry at the C8 and/or C9 positions. A hydrogen atom at C8 of the steroids of the invention is typically in the xcex2 configuration. In addition, preferred steroids of the invention may have methyl substituents with p stereochemistry at the C10 and/or C13 positions. Compounds of the invention preferably have a C14 hydrogen with the xcex1 stereochemistry when C15 is not a ketone. In preferred steroids of the invention that have a substituent at C17, the C17 substituent has xcex2 stereochemistry.
Steroids having 6,7-dioxygenation in the B-ring according to Structure 2 can be synthesized from a number of commercially available steroidal precursors having an xcex1,xcex2-unsaturated carbonyl group in the A-ring, including 4-androsten-3,17-dione (compound 1 below) and dehydroisoandrosterone (compound 247 below). These specific steroid precursors are available from Steraloids Inc., Wilton, N.H. Other suitable steroid precursors having C3 oxygen functionalities and xcex945 carbon-carbon double bonds may be obtained from, e.g., Aldrich Chemical Co., Milwaukee, Wis.
An exemplary synthetic sequence to prepare a compound of Structure 2 from 4-androsten-3,17-dione is summarized in Scheme 1 below. 
Initially, the carbonyl functionalities of 4-androsten-3,17-dione are protected by carbonyl protecting groups. As shown in Scheme 1, this may be accomplished by reacting compound 1 with a benzene solution of (CH2OH)2 and p-TsOH, thereby converting the carbonyl groups to ketal groups. Other suitable carbonyl protecting groups are listed in Greene, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, New York, N.Y. (1981). Under the acidic conditions which form the protected ketone groups, there occurs concomitant migration of the C4-C5 carbon-carbon double bond to the C5-C6 position, to ultimately form compound 2.
Allylic oxidation of the C5-C6 carbon-carbon double bond of compound 2 introduces a carbonyl oxygen at C7, to thereby form compound 3. A number of oxidizing agents and experimental conditions can be used for this allylic oxidation, including chromium trioxide/3,5-dimethylpyrazole complex, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), or RuCl3 and t-butylhydroperoxide.
Reduction of the resultant C7 ketone with an appropriate reducing agent gives the hydroxyl functionality at C7, as shown in compound 4. Any of several metal hydride reducing agents can be used for this task including sodium borohydride or lithium aluminum hydride. Generally, reduction of the C7 ketone produces the xcex2-OH configuration by hydride attack from the least hindered face of the steroid. The C7 hydroxyl group is then preferably protected with an hydroxyl protecting group, e.g., t-butyldimethylsilane (TBDMS), to provide a protected allylic alcohol as in compound 5. Other suitable hydroxyl protecting groups are listed in Greene, supra.
Introduction of the C6 oxygen can be achieved, before or after protection of the C7 hydroxyl group, by methods such as hydroboration/oxidation or epoxidation followed by ring opening. For example, the xcex945 carbon-carbon double bond of compound 5 can be epoxidized with any of a number of peracids including m-chloroperbenzoic acid, trifluoroperacetic acid or 3,5-dinitroperoxybenzoic acid, to provide an epoxide such as in compound 6. Generally, the epoxide introduced has the xcex1-configuration arising from attack on the least hindered face of the steroid ring structure. Subsequent ring opening of the epoxide can be accomplished under acidic conditions, such as 80% aqueous acetic acid at 60xc2x0 C. The crude mixture contains both compound 7 (having an allylic alcohol at the C6 position with the xcex1-configuration) and the C7 silyl derivative thereof. This crude mixture can be treated with tetrabutylanmmonium fluoride (TBAF) in tetrahydrofuran (THF) to give a single compound (7). Alternatively, hydroboration of the xcex945 double bond with an appropriate borane complex followed by oxidation using reagents such as basic hydrogen peroxide will also introduce an hydroxyl group in the xcex1-configuration at C6.
Compound 7 is exemplary of compounds having the oxygenation pattern of Structures 2 and 3. The methodology by which compound 1 may be converted to a compound of Structures 2 and/or 3 is generally applicable to a wide variety of compounds having an xcex1,xcex2-unsaturated carbonyl group in the A-ring of a steroid. Additional compounds of Structures 2 and/or 3 may be prepared by modification of a dihydroxy compound such as compound 7. In such case, it may be necessary to protect each of the C6 and C7 hydroxyl groups, and methodology to achieve such protection is described later herein.
Compound 7 or an analog thereof may be converted to a compound of Structure 4. Essentially, this may be accomplished by protecting the C6 and C7 hydroxyl groups and the C17 carbonyl group, and then reducing the xcex944 carbon-carbon double bond. Lithium in ammonia/THF is an example of a suitable reducing agent. Such a reduction provides an enolate, which may be trapped with a suitable electrophile, e.g., trimethylsilyl chloride or diethylchlorophosphate.
An example of such a conversion is shown in Scheme 2. Thus, protection of the C6 and C7 hydroxyl groups of compound 7 may be accomplished by treatment with 2,2-dimethoxypropane and a catalytic amount of (1S)-(+)-10-camphorsulfonic acid (CSA) to produce acetonide 8. The C17 carbonyl group of compound 8 may be protected by converting it to an hydroxyl group, and then protecting the hydroxyl group. Chemoselective reduction of the C17 carbonyl group may be accomplished by use of NaBH4 in methanol to provide compound 9, which in turn is reacted with a suitable hydroxyl protecting group, e.g., t-butyldimethylsilyl chloride, to provide silyl ether compound 10. Compound 10 may be reacted with lithium in liquid ammonia/THF, followed by quenching with diethylchlorophosphate, to provide compound 11. Compound 11 has a 5xcex1 hydrogen, as well as C6 and C7 dihydroxylation, and thus is a representative compound of Structure 4. 
In an aspect of the present invention, olefinic steroids having an exocyclic olefin at C17 and oxygen atoms at both C6 and C7 are provided. In one embodiment, the olefinic steroid has the Structure 5, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 5 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10 and C13 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C14 is substituted with xe2x80x94X, xe2x80x94OR1, or xe2x80x94R4 excluding methyl;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R2, R3 and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
Providing an exocyclic double bond at C17 is readily accomplished by the Wittig reaction, starting with a C17 carbonyl compound. Steroids of the invention having C17 carbonyl functionality are readily available, e.g., in compound 7 as prepared according to Scheme 1, or by the synthetic sequence summarized in Scheme 3 below, which starts from compound 10 (as prepared in Scheme 2). 
Thus, the A-ring of compound 10 can be reduced to afford a C3 carbonyl group as the only functionality in the A-ring. Scheme 3 illustrates a two-step sequence to achieve this reduction, wherein compound 10 is reduced with lithium in liquid ammonia and an ether solvent, e.g., diethyl ether or THF, to provide a mixture of compounds 12 and 13. This mixture may then be oxidized with a suitable oxidizing agent, for example PDC, to give exclusively compound 13. Compound 13 may then be reduced with LS-Selectride(copyright) (Aldrich Chemical Co., Milwaukee, Wis.) or other selective reducing agent, to provide compound 14 having the indicated stereochemistry.
The 3xcex1-hydroxyl group of compound 14 may then be protected as the acetate using acetic anhydride and pyridine to give compound 15. Other suitable hydroxyl protecting groups could be used instead of the acetate group. Removal of the silyl protecting group at C17 can be achieved under standard conditions known in the art for removing this silyl protecting group, e.g., using tetrabutylammonium fluoride (TBAF), to afford a C17 hydroxyl compound such as compound 16. The C17 hydroxyl group can be oxidized to a carbonyl group under typical oxidation conditions, e.g., using oxalyl chloride in DMSO and Et3N, to provide ketone compound 17.
Compound 17 can be used in a multitude of olefination reactions, including Wittig-type reactions, to provide compounds of Structure 5 having an olefin at C17. For example, compound 17 may be reacted with ethyltriphenylphosphonium bromide to provide the ethylidene compound 18. Other starting ketones may be used to provide other steroids having an exocyclic double bond at C17.
As described previously, compounds containing a carbonyl at C17 (or those that contain functionality that is readily converted to a carbonyl group) can be transformed into compounds containing a carbon-carbon double bond at C17 using Wittig chemistry. For example, as outlined in Scheme 4 below, compound 19 may be transformed into the corresponding C17 ethylidene compound 23 in a five step process. Thus, the 2xcex1,3xcex2-dihydroxy functionality of compound 19 may be protected with hydroxyl protecting groups, (e.g., using 2,2-dimethoxy propane and camphor sulfonic acid (CSA) in N,N-dimethylformamide (DMF) to give a compound such as compound 20. Deprotection of the C17 hydroxyl may be achieved using reaction conditions suitable for the particular hydroxyl protecting group (in this instance, TBAF in THF may be used) followed by oxidation of the resulting hydroxyl group (e.g., using PDC in CH2Cl2) yields the compound containing the C17 ketone (21). Reaction of compound 21 with a Wittig reagent, e.g., ethyl triphenyl phosphonium bromide and potassium t-butoxide in toluene, gives compound 22. Deprotection of the hydroxyl groups in olefin 22 affords the tetrahydroxy compound 23. 
Protection steps may be required prior to derivatization at C17 in some cases. For example, in compound 24 (prepared according to Scheme 14) the C3 ketone should first be protected before proceeding with the transformations at C17 (see Scheme 5 below). Thus, compound 24 may first be reduced (e.g., by reaction with NaBH4 in ethanol) then acylated (e.g., using acetic anhydride in pyridine) to yield the C3,C5-acetoxy derivative 25. Deprotection, oxidation and Wittig chemistry at C17, analogous to that described in Scheme 4 may be used to provide compound 27. Subsequent deprotection of the C6 and C7 hydroxyl groups (80% acetic acid is conveniently used to remove the ketal group of compound 27) gives compound 28 which contains the exocyclic xcex9417 olefin. 
In an aspect of the present invention, steroids having C17 oxygenation as well as oxygenation at C6 and C7 are provided. In one embodiment, the steroid has the Structure 6, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 6 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
R5 and R6 may together form a direct bond so C17 is a carbonyl group, or may together with C17 form a cyclic 3-6 membered ether or 4-6 membered lactone; otherwise R1 is R4 or xe2x80x94OR6 and R6 is R1 or R4; and
X represents fluoride, chloride, bromide and iodide.
Preferably, neither the A nor B ring in compounds of Structure 6 is aromatic. In another preferred embodiment, when C10 is substituted with methyl, then C5 is not directly bonded to an oxygen atom.
Many examples of compounds of Structure 6 and their synthesis have already been provided above. For instance, compounds 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 24, 25 and 26 are representative compounds of Structure 6. Many additional compounds of Structure 6, including the synthesis thereof, are provided herein in connection with other compounds of the invention. Therefore, one of ordinary skill in the art is able to prepare many compounds of Structure 6 in view of the disclosure herein.
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C1. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C1 for a compound of Structure 6 is provided below and outlined in Schemes 6, 7, and 8. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C1 for any compound of Structures 5-12 where C1 oxygen and/or hydrocarbon substitution is desired.
Introduction of an oxygen functionality at C1 of the steroid carbon skeleton can be accomplished by first generating the 1-ene-3-one functionalization pattern in the A-ring of a steroid, followed by Michael addition chemistry using any of a number of alkoxide anions, as outlined in Scheme 6. For example, the enone 29 may be produced from compound 13 using standard methodology. The benzyloxy compound 30 may then be produced by reacting the enone (29) with benzyl alcohol and KOH. Reduction of the C3 ketone of compound 30, and protection of the resultant secondary alcohol as the silyloxy derivative (to provide compound 31) may be followed by catalytic hydrogenation to yield the C1 hydroxyl functionality in compound 32. Oxidation of this secondary alcohol using, e.g., PDC in CH2Cl2 may produce compound 33 having a C1 ketone. 
Compounds containing both an alkyl group and an hydroxyl group at C1 may be produced by reaction of compound 33 with an alkyl lithium reagent. For example, reaction of compound 33 with CH3Li in ether will provide the tertiary alcohol in compound 34 (Scheme 7). 
Michael addition chemistry similar to that described in Scheme 6 can be used to add an alkyl group to the C1 position. This can be accomplished using a number of reagents including R2CuLi where R may be alkyl, vinyl or aryl. For example, compound 29 may be reacted with Me2CuLi in ether to yield the C1 methyl substituted derivative 35 (Scheme 8). 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C2. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C2 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C2 for any compound of Structures 5-12 where C2 oxygen and/or hydrocarbon substitution is desired.
Compounds containing oxygen at C2 may be prepared in a number of ways including hydroboration of a silyl enol ether as shown in Scheme 9. The silyl enol ether may be prepared from the enone 29 via Li/NH3 reduction followed by trapping of the resultant enolate using TMSCl to yield compound 36 (or other R3SiCl reagents to produce an analogous silyl enol ether). Hydroboration of the carbon-carbon double bond in 36 may give the 2xcex1,3xcex2-dihydroxy functionalization pattern (compound 19). Oxidation of this dihydroxy compound using PDC in CH2Cl2 may provide the diketone 38. 
Preparation of C2 hydrocarbon substituted compounds can be produced, e.g., by xcex1-alkylation of a compound containing a C3 ketone functionality. For example, Li/NH3 reduction of the enone 29 followed by trapping the resultant anion with an alkylating agent provides C2 alkylation. Treatment of the resultant enolate with methyl iodide may yield the C2 methylated compound 39 (Scheme 10 below). This methodology can be applied to a variety of different compounds using a number of different alkyl halides. 
Compounds of Structure 6 may have hydrocarbon substitution at C3. Exemplary synthetic methodology to provide hydrocarbon substitution at C3 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C3 for any compound of Structures 5-12 where C3 hydrocarbon substitution is desired.
Wittig chemistry on compound 13 followed by reduction of the double bond or alternative modifications will provide the alkyl or dialkyl derivative at C3. For example, reaction of compound 13 with methyl triphenylphosphonium bromide and tBuOK in toluene may be used to give compound 40 (Scheme 11). A Simmons-Smith reaction on compound 40 with CH2I2 and Znxe2x80x94Cu followed by catalytic hydrogenolysis of the cyclopropane derivative 41 using H2, Pd/C in ethanol can be used to give the dialkyl derivative 42 (Scheme 11). 
Compounds of Structure 6 may have hydrocarbon substitution at C4. Exemplary synthetic methodology to provide hydrocarbon substitution at C4 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C4 for any compound of Structures 5-12 where C4 hydrocarbon substitution is desired.
Alkylation at C4 may be achieved by first producing the enolate anion from the enone in compound 10 (using, for example, reduction with lithium in liquid ammonia) followed by treatment with an appropriate alkyl halide as shown in Scheme 12. 
Alternatively, Compounds of Structure 6 may have carbonyl functionality at C4. Exemplary synthetic methodology to provide carbonyl functionality at C4 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide carbonyl functionality at C4 for any compound of Structures 5-12 where a C4 carbonyl group is desired. As described below, the carbonyl functionality at C4 provides a convenient entry into compounds having a tertiary alcohol and a hydrocarbyl group at C4.
Compounds with a ketone (carbonyl) functionality at C4 may be prepared from compound 44 (which in turn is prepared from a deacetylation of acetate 147 from Scheme 44) by selectively tosylating, epoxidation and then epoxide ring opening followed by oxidation of the resultant 4xcex2-hydroxyl functionality. For example, as illustrated in Scheme 13, treatment of the diol 44 with p-toluenesulfonyl-chloride in pyridine and DMF followed by reaction of the resultant tosylate 45 with tBuOK can introduce the 3xcex2,4xcex2-epoxide (compound 46). Treatment of the epoxide with Me2CuLi gives the 3xcex1-methyl derivative 47 and subsequent oxidation using, for example, PDC in CH2Cl2 gives the desired ketone (carbonyl) at C4 (compound 48). Epimerization to the 3xcex2-methyl derivative can be achieved using tBuOK in tBuOH and subsequent treatment of the ketone with a methyl lithium in THF can provide the tertiary alcohol at C4 (compound 49). 
Alternatively, compounds of Structure 6 may have oxygen or hydrocarbon substitution at C5. Exemplary synthetic methodology to provide oxygen or hydrocarbon substitution at C5 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen or hydrocarbon substitution at C5 for any compound of Structures 5-12 where C5 oxygen or hydrocarbon substitution is desired.
Epoxidation of compound 10 followed by ring opening can be used to generate a hydroxy and subsequently an alkoxy substitution at C5 of the carbon skeleton. For example, epoxidation of the double bond in compound 10 can yield the corresponding epoxide derivative 50 which may be readily converted to the tertiary hydroxyl compound 24 (Scheme 14 below). Subsequent reduction of compound 24 using NaBH4 in THF and methylation using MeI in the presence of tBuOK in THF can give the diacetoxy compound 51 (Scheme 15 below). Alkyl substitution at C5 may be achieved using an appropriate alkyl copper lithium reagent. For example, treatment of compound 10 with (CH3)2CuLi in ether may produce the C5 methyl derivative 52 (Scheme 16). 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C9. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C9 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C9 for any compound of Structures 5-12 where C9 oxygen and/or hydrocarbon substitution is desired.
Hydroxylation at the C9 position may be achieved by reaction of a xcex949,11 olefinic compound with m-chloroperbenzoic acid followed by reduction with LiAlH4, as outlined in Scheme 17. For example, using this procedure, compound 53 (prepared from the dehydration of compound 60; e.g., NaH, CS2, MeI, heat) may be used as the starting material to produce compound 54 which, upon reduction of the epoxide can produce the C9 hydroxyl-containing derivative 55. Subsequent reaction of the tertiary alcohol in compound 55 with dimethyl sulfate in aqueous sodium hydroxide may be used to give the corresponding alkoxy derivative, compound 56. 
Alternatively, compounds of Structure 6 may have hydrocarbon substitution at C9. Exemplary synthetic methodology to provide hydrocarbon substitution at C9 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C9 for any compound of Structures 5-12 where C9 hydrocarbon substitution is desired.
Cyclopropanation of compound 53 using CH2I2 and Znxe2x80x94Cu followed by catalytic hydrogenation may provide the corresponding C9-alkyl substituted compound 57 (Scheme 18). 
Alternatively, compounds of Structure 6 may have halide substitution at C9. Exemplary synthetic methodology to provide halide substitution at C9 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide halide substitution at C9 for any compound of Structures 5-12 where C9 halide substitution is desired.
Introduction of a halogen atom at C9 can be achieved in a number of ways including reaction of a C9 tertiary alcohol (see, e.g., compound 55 in Scheme 17) with thionyl chloride. Thus, reaction of compound 55 with SOCl2 in CH2Cl2, may be used to provide the chloro derivative 59 as shown in Scheme 19. 
Compounds of Structure 6 preferably have a methyl substituent at C10. However, the C10 position may be derivatized so as to have many functional groups other than methyl. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C10 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C10 for any compound of Structures 5-12 where C10 oxygen and/or hydrocarbon substitution is desired.
The derivatization of the C10 position may be achieved via the route shown in Scheme 20. A 10xcex2-hydroxy steroid 60 (prepared, for example, as outlined in Scheme 22 below) may be derivatized using nitrosyl chloride (NOCl) in pyridine to yield a nitrite derivative such as 61. Irradiation of the nitrite 61 then can lead to a mixture of the oximes 62 and 63. Compound 63 is reduced to the corresponding imine 64 by treatment with aqueous TiCl3 in dioxane and acetic acid. The hemiacetal acetate 65 may be produced upon treatment of 64 with NaNO2 in aqueous acetic acid. This can also lead to deprotection of the 6,7-hydroxyl groups. The acetonide can be reintroduced by reaction of the crude product with 2,2-dimethoxypropane and camphor sulfonic acid. Alkaline hydrolysis (NaOH, MeOH) to give the hydroxy aldehyde 66 is followed by protection of the secondary alcohol at C11 as the benzyl ether using BnBr, NaH in DMF to afford compound 67. 
A Grignard reaction of compound 67 with CH3MgBr followed by PDC oxidation in CH2Cl2 then by a Bayer-Williger oxidation with m-chloroperbenzoic acid in methylene chloride can give the C10 acetoxy derivative 68. Removal of the acetate group may be accomplished with base, for example, sodium methoxide in methanol, to give the C10-xcex2 alcohol 69. This C10 hydroxyl group may then be further derivatized to the alkoxide analogue 70, using, for example, sodium hydride in THF followed by treatment with an alkylating agent such as methyl iodide. Alternatively, conversion of the C10 hydroxyl group in compound 69 to the corresponding chloride derivative 71 is achieved using a chlorinating agent, e.g., thionyl chloride, as shown in Scheme 21. 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C11. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C11 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C11 for any compound of Structures 5-12 where C11 oxygen and/or hydrocarbon substitution is desired.
The preparation of compounds of Structure 6 containing an oxygen function at the C11 position may be achieved according to the pathway shown in Scheme 22 from the commercially available starting material 72 and related compounds. 
If starting with a steroid having a hydroxyl group in the A-ring, as in compound 75 (prepared from the commercially available compound 72 (Scheme 22)), removal of the C3 hydroxyl may be achieved using a two step procedure involving preparation of the methyl xanthate using NaH, CS2 and CH3I in THF followed by nBu3SnH reduction and deprotection (80% AcOH) to yield compound 77. After reduction and protection of the C17 ketone using NABH4 in methanol followed by TBDMSCl and imidazole in DMF, oxidation of the C7 position can be achieved using a number of oxidizing conditions such as CrO3 and 3,5-dimethylpyrazole in CH2Cl2 or RuCl3 and tBuOOH in H2O and cyclohexane. Subsequent reduction (NaBH4, CeCl3, THF-MeOH) of the C7 ketone and acetylation can provide the C7 acetoxy derivative 80. Hydroboration of compound 80 provides a product with the 6xcex1,7xcex2,11xcex2-hydroxylation pattern as in triol 81. Protection of the 6xcex1,7xcex2 hydroxyls in compound 81 using 2,2-dimethoxypropane in the presence of camphor sulfonic acid (CSA) followed by oxidation using PDC in CH2Cl2 gives compound 82 which contains the C11 ketone.
Compounds of Structure 6 may alternatively or additionally have hydrocarbon substitution at C11. Exemplary synthetic methodology to provide hydrocarbon substitution at C11 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C11 for any compound of Structures 5-12 where C11 hydrocarbon substitution is desired.
Conversion of the compound 82 C11-ketosteroid to a quaternary alkyl center may be accomplished as shown in Scheme 23 below. 
Thus, the C11-ketosteroid 82 in toluene may be added to a solution of methyl triphenylphosphonium bromide and tBuOK to afford compounds with a xcex9411 carbon-carbon double bond such as 83. Subsequent treatment of the compound 83 with CH2I2, Znxe2x80x94Cu may give the cyclopropyl derivative 84. Hydrogenation of the cyclopropane ring (H2, Pd/C in ethanol) may give the dialkyl derivative 85. Other Wittig reagents may be employed to make analogous alkyl-substituted steroids.
Monoalkylation of the C11 position may be achieved by application of Wittig chemistry on compounds with a C11 ketone, as described above, followed directly by catalytic hydrogenation (as illustrated in Scheme 24). For example, catalytic hydrogenation (H2, Pd/C in ethanol) on compound 83 affords the C11 methylated steroid 86. 
Compounds of Structure 6 may have halide substitution at C11. Exemplary synthetic methodology to provide halide substitution at C11 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide halide substitution at C11 for any compound of Structures 5-12 where C11 halide substitution is desired.
Thus, halogenation of the C11 position may be achieved according to the route shown in Scheme 25. For example, treatment of compound 60 with a halogenating agent, e.g., thionyl chloride in CH2Cl2, gives the corresponding 11xcex2-chloro derivative 87. In general, hydroxyl functionality may serve as a precursor to halide functionality. 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C12. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C12 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C12 for any compound of Structures 5-12 where C12 oxygen and/or hydrocarbon substitution is desired.
Placement of an oxygen function at the C12 position may be achieved as illustrated in Scheme 26. 
Thus, a C11 ketosteroid, such as compound 82, may be reacted with LDA in THF followed by trapping of the enolate anion with (Me2N)2P(O)Cl followed by reduction of the enolphosphate using Li and EtNH2 to provide a compound, such as 88, with a xcex9411,12 carbon-carbon double bond. Epoxidation may be achieved using an epoxidizing agent, e.g., mCPBA in CH2Cl2, to give the corresponding 11xcex1,12xcex1-epoxide derivative 89. Subsequent LiAlH4 reduction of the epoxide can form the 12xcex1-hydroxy derivative (90) which can be oxidized using the appropriate oxidizing agent, for example, pyridinium dichromate (PDC) in methylene chloride to give the desired C12 ketosteroid 91.
Compounds of Structure 6 may have hydrocarbon substitution at C12. Exemplary synthetic methodology to provide hydrocarbon substitution at C12 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C12 for any compound of Structures 5-12 where C12 hydrocarbon substitution is desired.
Alkyl groups, such as methyl, may be introduced into the C12 position as shown in Scheme 27 below. The C11 ketosteroid 82, (prepared, for example, according to Scheme 22), and a strong base, e.g., lithium diisopropylamide in THF, are combined and treated with an alkylating agent, e.g., methyl iodide, to afford the C12 methylated product 92. At this stage, the C11 ketone can be removed using a number of methods including those described in connection with Scheme 26 to give the monomethylated product 93. Further treatment with strong base and an alkylating agent, e.g., lithium diisopropylamide and methyl iodide, gives the C12 dimethylated product 94. Again, this compound may be subjected to reducing conditions to remove the C11 ketone group thus giving the C12 dimethyl derivative 95. 
Compounds of Structure 6 may have oxygen and hydrocarbon substitution at C12. Exemplary synthetic methodology to provide oxygen and hydrocarbon substitution at C12 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and hydrocarbon substitution at C12 for any compound of Structures 5-12 where C12 oxygen plus hydrocarbon substitution is desired.
Scheme 28 shows the preparation of a tertiary alcohol at the C12 position from the corresponding C12 ketone. In Scheme 28, the C12 ketone 91 is treated with a alkyl lithium reagent, e.g., methyl lithium in diethyl ether, to give the desired tertiary alcohol 96. 
Compounds of Structure 6 may have carbon, oxygen or halogen, to name a few atoms, bonded to C13. Exemplary synthetic methodology to provide such substitution at C13 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide the same or analogous substitution at C13 for any compound of Structures 5-12 where such C13 substitution is desired.
Substituents at the C13 position may be introduced according to the pathway shown in Scheme 29 below. In a fashion similar to that previously described in Scheme 20, the C13 position can be substituted with a hydrocarbyloxy moiety, e.g., a methoxy moiety. Thus, the oxime derivative 62, (prepared, for example, as described in Scheme 20), is reduced to the corresponding imine 97 by treatment with aqueous TiCl3 in dioxane and acetic acid. The hemiacetal acetate 98 may be produced upon treatment of compound 97 with NaNO2 in aqueous acetic acid. Alkaline hydrolysis (NaOH, MeOH) to give the hydroxy aldehyde 99 is followed by protection of the secondary alcohol at C11 as the benzyl ether using BnBr, NaH in DMF to afford compound 100. 
A Grignard reaction on compound 100 may be used to introduce additional functionality at C13. For example, treatment of compound 100 with methyl magnesium bromide, followed by oxidation of the resulting C13 secondary alcohol gives the methyl ketone substituent at C13. This may be oxidized, e.g., using Bayer-Williger oxidation with m-chloroperbenzoic acid in methylene chloride, to give the C13 acetoxy derivative 101. This ester may be hydrolyzed by treatment with sodium methoxide in methanol to produce the tertiary alcohol 102. Subsequent reaction of the alcohol with sodium hydride in THF followed by its quenching with methyl iodide may be used to produce the C13 mrethoxysteroid 103. Other alkylating agents could be used to prepare other hydrocarbyloxy derivatives. The C13 hydroxyl moiety may then be converted to a halide, for example a chloride, by the reaction of alcohol 102 with thionyl chloride, thus affording the C13 chlorosteroid 104, as shown in Scheme 30 below. 
Compounds of Structure 6 may have hydrocarbon substitution at C14. Exemplary synthetic methodology to provide hydrocarbon substitution at C14 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide hydrocarbon substitution at C14 for any compound of Structures 5-12 where C14 hydrocarbon substitution is desired.
For example, introduction of an alkyl group at C14 of the steroid carbon skeleton could be accomplished by alkylation at the C14 position. One approach to achieve such an alkylation is shown in Scheme 31 below. Initially, preparation of the enone 107 can be accomplished by deprotection (TBAF, THF) of compound 105 followed by oxidation of the secondary alcohol using PDC in CH2Cl2 to give the C17 ketone derivative 106. Conversion of the ketone 106 to the enone 107 may be achieved using isopropenyl acetate and pTsOH to produce the intermediate enol acetate followed by production of the enone using reagents set forth in Scheme 31. This is followed by conversion of the enone 107 to the silyl enol ether 108 by reacting enone 107 with lithium diethylamide in THF followed by reaction of the resultant anion with triisopropylsilyl triflate (TIPSOTf). The cyclopropane derivative 109 is then prepared from silyl ether 108 using CH2I2 and Znxe2x80x94Cu. Deprotection of the silyl enol ether and cleavage of the cyclopropane ring is achieved using TBAF in THF followed by tBuOK in DMSO and aqueous work-up procedures. 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C15. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C15 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C15 for any compound of Structures 5-12 where C15 oxygen and/or hydrocarbon substitution is desired.
For example, introduction of an oxygen functionality at C15 of the steroid carbon skeleton could be accomplished by Michael addition type chemistry using any of a number of alkoxide anions. As outlined in Scheme 32 below, the 4-methoxybenzyloxy compound 111 (a representative C15-hydrocarbyloxy steroid derivative of the invention, where the 4-methoxybenzyloxy group (MPMO) serves as an hydroxyl protecting group) could be produced by reacting the enone 107 with 4-methoxybenzyl alcohol and base (e.g., powdered KOH). The 4-methoxybenzyl protecting group may be removed under oxidizing conditions, e.g., by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation, to yield the C15 hydroxyl group (compound 112). When this is followed by oxidation of the secondary alcohol (using, for example, PDC in CH2Cl2), the corresponding C15 ketone (compound 113) may be produced. 
Compounds containing an alkyl group at C15 may also be produced by a Michael type conjugate addition. For example, reaction of compound 107 with an organolithium cuprate (e.g., Me2CuLi) in Et2O may be used to produce the methyl derivative 114 as shown in Scheme 33. 
Compounds containing both a hydrocarbyl (e.g., an alkyl) group and a hydrocarbyloxy (e.g., an alkoxy) group at C15 can be produced by using Grignard chemistry on compound 117, as outlined in Scheme 34 below. Compound 117 may be prepared in a three step process involving the reduction (e.g., nBu3SnH reduction of a methyl xanthate prepared from the C17 hydroxy analog of compound 111) to afford steroid 115, followed by oxidative removal (e.g., using DDQ) of the MPM protecting group yielding the secondary alcohol derivative 116. Subsequent oxidation of compound 116 to the corresponding ketone yields compound 117. A Grignard reaction on compound 117 using an alkylmagnesium bromide reagent (e.g., CH3MgBr) in ether produces the tertiary alcohol 118. Methylation of the tertiary alcohol in 118 with an alkylating agent (e.g., CH3I (note that an acylating agent can be used in place of an alkylating agent, in Scheme 34 and in every Scheme herein having an alkylating agent)) in the presence of base (e.g., K2CO3) yields the tertiary methoxy compound 119. 
Compounds of Structure 6 may have oxygen and/or hydrocarbon substitution at C16. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C16 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C16 for any compound of Structures 5-12 where C16 oxygen and/or hydrocarbon substitution is desired.
Introduction of a tertiary hydroxyl group at C16 of the steroid carbon skeleton may be accomplished using Grignard chemistry on compound 121 as shown in Scheme 35 below. The ketone 121 may be produced via hydroboration of the olefin (using, for example, Sia2BH in THF then aqueous NaOH, H2O2) of compound 308 (prepared from compound 106 as outlined in Scheme 35) to afford alcohol 120. The desired C16 ketone functionality may then generated by oxidizing the secondary alcohol at C16, using, for example, PDC in CH2Cl2, to yield compound 121. Reaction of the ketone 121 with a Grignard reagent, e.g., CH3MgBr in ether, may be used to produce the corresponding tertiary alcohol derivative, in this example, compound 122. The corresponding alkoxy derivative 123 could then be produced directly from compound 122 using the appropriate base and alkyl halide. 
Alkoxy groups at C16 may be produced directly from the corresponding C16 hydroxyl compound. For example, compound 124 may be produced by reacting compound 120 with an reagent, e.g., CH3I, and a base, e.g., K2CO3 (Scheme 36). 
C16 alkyl groups may be introduced by the direct alkylation of compounds that contain a C17 carbonyl. For example, reaction of compound 106 with CH3I and LDA (other strong bases and alkylating agents could be used) in THF yields the C16 methyl compound 125 (Scheme 37). 
Compounds of Structure 6 have oxygen and/or hydrocarbon substitution at C17, including tertiary alcohol and hydroxyl functionality. Exemplary synthetic methodology to provide tertiary alcohol and hydroxyl substitution at C17 for a compound of Structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide tertiary alcohol and hydroxyl substitution at C17 for any compound of Structures 5-12 where C17 tertiary alcohol or hydroxyl substitution is desired.
Thus, Grignard chemistry similar to that described in Scheme 34 may be used to add a tertiary alcohol functionality to the C17 position. For example, as outlined in Scheme 38 below, compound 106 may be reacted with CH3MgBr in ether to yield the tertiary alcohol derivative 126. Methylation of the resultant tertiary alcohol gives the corresponding C17 methoxy compound 127. Of course, other alkylating agents could be used to provide a wide range of hydrocarbyloxy compounds. 
In an aspect of the present invention, C5 stereodefined steroids having hydroxylation at C6 and C7, a 5xcex1 hydrogen and no oxygen atom bonded to C3 is provided. In one embodiment, the stereodefined steroid has the Structure 7, including individual enantiomeric or geometric isomers thereof and further including a solvate or pharmaceutically acceptable salt thereof. Structure 7 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C3 is substituted with one of xe2x95x90C(R4)(R4) and xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 wherein n ranges from 1 to about 6, or two of xe2x80x94X, and xe2x80x94R4;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represent a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In a preferred embodiment of compounds of Structure 7, C3 is not bonded to an oxygen atom. In another preferred embodiment, when C3 is substituted with two hydrogen atoms then C17 is not substituted with either xe2x80x94CH(CH3)(CH2)3CH(CH3)2 or xe2x80x94CH(CH3)(CH2)2C(xe2x95x90O)OCH3.
Compounds of Structure 7 have hydroxylation at C6 and C7 and a 5xcex1 hydrogen. A synthetic sequence for the preparation of compounds having these structural features has been set forth above, in Scheme 2, which shows the preparation of compound 11. While compound 11 has an oxygen atom bonded to C3, and is thus not a representative compound of Structure 7, compound 11 can be converted to a compound of Structure 7. Thus, as shown in Scheme 39 below, compound 11 may be reduced to compound 128, where lithium in liquid ammonia/t-butanol may be used to afford the desired reduction. Hydrogenation of compound 128 can provide compound 105, having a xe2x80x94CH2xe2x80x94 group at C3 as also shown in Scheme 39. 
As illustrated in Scheme 40, compound 128 may alternatively be converted to additional compounds of Structure 7. Thus, the C17 protected hydroxyl group of compound 128 may be deprotected to yield compound 129, and then the C17 hydroxyl group of compound 129 may be oxidized to a C17 carbonyl group as in compound 106. 
Compounds of Structure 7 containing a methylene at C3 may be obtained from compounds with an hydroxyl, protected hydroxyl or ketone functionality at C3. The same or analogous synthetic methodology may be used to prepare compounds of any of Structures 5-12 wherein a methylene group at C3 is desired.
For example, Scheme 39 above describes the conversion of compound 11 to compound 105 using chemistry described earlier. Thus, the chemistry described in connection with the Schemes herein can be extended to include compounds containing a methylene rather than an hydroxyl or carbonyl group at C3. In some cases, however, a series of protection and/or deprotection steps is first required.
Scheme 41 shows an example where the C3 silyloxy functionality must first be deprotected prior to the deoxygenation reaction. The TBDMS group in compound 31 may be removed using TBAF in THF. Preparation of the methyl xanthate derivative of compound 130 using KH, CS2 and MeI is followed by nBu3SnH reduction gives the compound (131) containing a methylene group at C3 and a protected hydroxyl group at C1. Oxidation to the C1 ketone is then achieved by removal of the C1 protecting group followed by using a suitable oxidizing agent, e.g., PDC in CH2Cl2, to give compound 132. 
Compounds of Structures 5-12, including Structure 7, having C3 alkyl functionality may be obtained by Wittig chemistry (prepared from the C3 ketone as described in connection with Scheme 11). A number of Wittig reagents can be used for this purpose giving rise to substituents with various chain lengths and branching.
In an aspect of the present invention, demethylated steroids are provided which have oxygen and/or hydrocarbon substitution at C6 and C7, however do not have methyl groups at both of C10 and C13. In one embodiment, the demethylated steroid has the Structure 8, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 8 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
with the provisos that (a) C10 and C13 are not simultaneously substituted with methyl, and (b) when C10 is substituted with methyl, then C14 is not substituted with a methyl;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represent a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In a preferred embodiment, compounds of Structure 8 do not have aromatic A rings.
A number of examples of compounds containing substituents other than methyl at C10 or C13 are described herein in connection with Schemes 20, 29 and 30. The substituents include carbonyl, hydroxymethylene, methoxy, ketal, lactone carbonyl, aldehyde, hydroxy, etc. Not described in connection with Schemes 20, 29 and 30 are compounds containing no substitution (i.e., merely hydrogen substitution) at C10 and/or C13. Below are examples discussing synthetic approaches to producing 19-nor-6xcex1,7xcex2-dioxygenated steroids.
The synthesis of many of the various compounds of the present invention has been detailed in connection with compounds 1 and 247, both commercially available starting materials. However, the preparation of analogous compounds, e.g., compound 141, that differs only in the lack of a C10 methyl substituent, can be achieved according to Scheme 42 shown below.
In Scheme 42, the starting material is the commercially available 19-nor-testosterone (133) (Steraloids Inc., Wilton, N.H., or Aldrich Chemical Company, Milwaukee, Wis.). Reduction of compound 133 using NaBH4 in ethanol may give compound 134 which contains the 3xcex2-hydroxyl group. After protection of the 3xcex2-hydroxyl group using TBDMSCl and imidazole in DMF, allylic oxidation on the resultant diprotected compound (135) may be used to afford the enone derivative 136. Reduction and acetylation, as described in previous Sections (Scheme 1), followed by hydroboration using BH3-THF and oxidative work up (H2O2, 30% NaOH), gives compound 138 which contains the 6xcex1,7xcex2,17xcex2-hydroxylation pattern. Protection of the 6xcex1,7xcex2-hydroxyls using 2,2-dimethoxypropane and camphor sulfonic acid can be followed by oxidation of the C17 hydroxyl group using PDC in CH2Cl2 to afford compound 140 containing the C17 ketone functionality. Reaction of compound 140 with the Wittig reagent prepared from ethyltriphenylphosphonium bromide and tBuOK in toluene gives the ethylidene derivative which can be deprotected in 80% acetic acid to yield the trihydroxy compound 141 which is identical to compound 333 except for the lack of a C10 methyl substituent. 
In an aspect of the present invention, polyoxygenated steroids having oxygen and/or hydrocarbon substitution at each of C3, C4, C6 and C7, where the oxygen and/or hydrocarbon substitution at C6 has the alpha stereochemistry and the oxygen and/or hydrocarbon substitution at C7 has the beta stereochemistry, are provided. In one embodiment, the polyoxygenated steroid has the Structure 9, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 9 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
with the proviso that C17 is not substituted with any of the following: 
each of C5, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C8 is substituted with xe2x80x94X or xe2x80x94R4 and is preferably not bonded directly to oxygen;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
Compounds having the oxygen and/or hydrocarbon substitution shown in Structure 9 may be prepared from compound 142, which was prepared as described below in Scheme 52. Thus, as shown in Scheme 43, compound 142 may be epoxidized with any number of epoxidization conditions, e.g., using m-chloroperbenzoic acid (m-CPBA) in dichloromethane, to provide the epoxide compound 143. Ring opening of the epoxide group using a mild organic acid (e.g., anhydrous acetic acid, which is preferred) provides compound 144, which is a representative compound of Structure 9. 
From compound 144, many other compounds of Structure 9 may be prepared. For example, as illustrated in Scheme 43, compound 144 may be deacetylated to provide the tetrahydroxy ketone compound 145. The ketone group at C17 may be subject to Wittig chemistry as discussed above, to provide entry into a large class of tetrahydroxy olefin compounds of Structure 9.
Structure 9, which has a 3,4,6,7-tetraoxygenation pattern, may additionally contain further oxygen-containing substituents. For example, compounds of Structure 9 may have an oxygen atom at C11. Synthetic methodology to introduce a C11 oxygen atom, which may be employed to prepare compounds of Structures 5-12 including Structure 9, may be achieved by chemistry shown in Scheme 44, or by chemistry analogous to that shown in Scheme 44.
For example, rather than using a commercially available starting material with a C11 hydroxyl functionality or xcex949,11 carbon-carbon double bond, the formation of the m-bischloroiodosobenzylformyl ester followed by its photolysis generates the desired unsaturation at the xcex949,11 position (compound 149). Thus, the C6 and C7 hydroxyls in compound 146 (prepared according to Scheme 61) may be protected using 2,2-dimethoxypropane and camphor sulfonic acid to give compound 147. Subsequent reaction of 147 with m-bischloroiodosobenzylformyl chloride in pyridine followed by photolysis in CCl4 gives compound 149. Protection of the A-ring hydroxyl groups followed by hydroboration/oxidation yields the C11 hydroxy derivative 151. Complete deprotection using 80% acetic acid gives the hexol 152. 
In an aspect of the present invention, steroid ketones having a pyran or xcex4-lactone ring in the C17 sidechain are provided. In one embodiment, the steroid ketone has the Structure 10, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 10 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
with the proviso that C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl, and are preferably not simultaneously substituted with oxygen atoms;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
G is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OR1)xe2x80x94, xe2x80x94C(R4)(OR1)xe2x80x94 or xe2x80x94C(OR1)(OR1)xe2x80x94;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
Convenient access to the C17 sidechain in compounds of Structure 10 begins with L-carvone, as shown in Scheme 45. 
L-Carvone (153) may be converted to compound 154 according to literature procedures. See, e.g., Tetrahedron Letters 25(41):4685-4688 (1984). The primary alcohol in compound 154 is then protected by, e.g., conversion to an acetate ester. Removal of the ketal protecting group in compound 155 using acidic conditions provides aldehyde 156.
The compound 156 can provide access to the C17 sidechain in compounds of Structure 10 as shown in Scheme 46 below. Thus, compound 145 as prepared in Scheme 43, may be treated with the ylid prepared from ethyltriphenylphosphonium bromide and base to afford compound 157 (used as starting material in Scheme 46). Thereafter, the four hydroxyl groups may be converted to protected hydroxyl groups, for example benzyloxy groups, as shown in compound 158. Compound 158 is then coupled with the aldehyde 156 (Scheme 45) in the presence of a Lewis acid, to provide compound 159. Deprotection of the C29 acetoxy group may then be accomplished with base to provide diol compound 160, which may then be oxidized to the xcex4-lactone compound 161. Allylic oxidation of compound 161 may introduce a carbonyl moiety at C15 with concurrent oxidation of the benzyl groups (Bn) to benzoate (Bz) groups, to form compound 162.
Reduction of the conjugated xcex9416 carbon-carbon double bond in the D-ring of compound 162 gives compound 163. Removal of the benzoate groups in 163 may be achieved using basic conditions (for example NaOMe in MeOH) with concurrent epimerization at C14 to yield product 164 which contains an epimeric mixture of the compounds containing the cis C/D ring junction and the trans C/D ring junction. Finally, protection of the C15 ketone followed by reduction of the xcex4-lactone to the lactol and deprotection (80% acetic acid) may be accomplished to give 22,29-epoxy-3,4,6,7,29-pentahydroxy-14xcex2-stigmastan-15-one (compound 165) and it""s C14 epimer 22,29-epoxy-3,4,6,7,29-pentahydroxy-14xcex1-stigmastan-15-one. 
Compounds of Structure 10 may have a C15 ketone and C22,29 epoxy functionality. In fact, compounds containing a variety of functionality in the A-D rings in addition to a C15 ketone and a sidechain hemiacetal may be produced using a combination of methodology described herein.
For example, as illustrated in Scheme 47, compound 176, which contains a methylene at C3, a carbonyl at C15 and a sidechain hemiacetal, may be produced by using methodology described herein. The C15 ketone and the sidechain hemiacetal may then be incorporated using methodology described in detail above (in connection with Schemes 45 and 46). 
As shown in Scheme 47, compound 76 can be deprotected using H2, Pd/C in ethanol to give a compound containing the C11 hydroxyl functionality which, upon heating in POCl3 and pyridine, may produce compound 167 containing the xcex949,11 double bond and its xcex9411,12 isomer. Epoxidation (of 167) using mCPBA followed by LiAlH4 reduction may be used to afford compound 169 which contains the C9 hydroxyl functional group. Protection of this hydroxyl group followed by removal of the ketal protecting group and Wittig chemistry may be done to yield the olefinic product 171. Conversion of compound 171 to lactol 176 may be accomplished using standard methods described herein.
A second example involves the preparation of derivative 186, a compound that contains the C15 ketone and the sidechain hemiacetal as well as a C1 hydroxyl functionality. Compound 186 may be produced in a multi-step procedure from the commercially available starting material 177 as shown in Scheme 48. The first step involves protection of compound 178 using e.g., ethylene glycol, pTsOH in benzene. Subsequent Michael addition using, e.g., benzyl alcohol and potassium hydroxide gives the C1 benzyloxy derivative 179. LS-Selectride(copyright) reduction of the ketone 179 followed by protection of the resultant alcohol as the benzyloxy derivative may be used to give compound 180. The conversion of compound 180 to lactol 186 may then be achieved using methods described in Scheme 47 and described in detail in other previous examples. 
Thus, the methodology described herein may be used to produce compounds with functionality at carbons in the steroidal ring structure as well as both the C15 ketone functionality and sidechain hemiacetal.
In a related aspect of the present invention, steroids having oxygenation at C6 and C7, with a pyran-or xcex4-lactone-containing sidechain at C17 are provided. In one embodiment, the steroid has the Structure 11, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 11 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
with the proviso that C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl, and are preferably not simultaneously substituted with oxygen atoms;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
G is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OR1)xe2x80x94, xe2x80x94C(R4)(0R4)xe2x80x94 or xe2x80x94C(OR1)(OR)xe2x80x94;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group: such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
The preparation of compounds of Structure 11 may be achieved using methodology set forth many places herein. For example, compounds 196 (Scheme 49) and 207 (Scheme 50) may be synthesized from compounds 30 and 55 in multi-step processes. Methods used to convert the C17 silyloxy group in compound 30 to the olefin 190 are analogous to those described in detail in previous examples, as are the methods used to convert compound 190 to compound 196. The same holds true for the conversions of compounds 55 to 200 and 200 to 207, respectively. 
The chemistry described in Schemes 49 and 50 above are just two examples of how the methods discussed herein may be applied to produce compounds containing a 6,7-dioxygenation pattern and the hemiacetal or xcex4-lactone sidechain. Thus, the methodology described previously may be used to produce compounds with functionality at C2, C4, C8, etc.
In an aspect of the present invention, steroid epoxides are provided. In one embodiment, the steroid epoxide has the Structure 12, including individual enantiomeric or geometric isomers thereof, and further including a solvate or pharmaceutically acceptable salt thereof. Structure 12 is defined as follows:
A compound of the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
Preferably, in compounds of Structure 12, C7 does not have carbonyl substitution when C5 has hydroxy or xe2x80x94OR1 substitution.
As with the previous examples, introduction of functional groups at various positions within the steroid ring structure of compounds containing a 3,4-epoxide group of Structure 12 may be achieved using methods described herein. For example, as shown in Scheme 51, an oxygen atom may be placed at C9 and/or C11, via epoxidation of xcex949,11 double bond.
Thus, LS-selectride reduction followed by remote oxidation using reagents described earlier on a compound such as compound 10 may provide an olefinic compound 208 (Scheme 51). Transformations to the xcex949,11 olefin can be achieved using standard methodology and concurrent reaction of both the xcex943,4 and xcex949,11 double bonds provide the desired epoxides at C3-C4 and C9-C11. Oxidation of the C3 hydroxyl moiety with PDC in CH2Cl2 then may be used to give the desired unsaturated A-ring (and optionally ring-opening the epoxide rings will provide a 3,6,7,9-polyhydroxylated steroid 215). 
The introduction of an alkyl group in the C16 position may also be achieved using similar chemistry described above. In the following example (Scheme 52), a methyl group is incorporated into this position from the condensation of the D-ring enolate with methyl iodide. This methodology is analogous to that described in connection with Scheme 37. As shown in Scheme 52, the alkylated epoxide 218 may be subjected to epoxide-ring-opening conditions to afford a 3,4,6,7-tetrahydroxy steroid 220. 
Compounds having 6xcex1,7xcex2-hydroxylation pattern have been discussed in detailed previous sections. Alternatively, compounds containing other stereochemistries at C6 and C7 may also be produced as discussed in the following section. For example, selective tosylation of compound 221 (prepared according to Scheme 73) using pTsCl in pyridine followed by treatment with potassium carbonate may yield the epoxide containing compound 223. Subsequent ring opening using aqueous acid may yield compounds with the 6xcex2,7xcex1 stereochemistry as shown in Scheme 53. 
Compounds with the 6xcex1,7xcex1 stereochemistry can be prepared from commercially available starting materials as shown in Scheme 54. Thus, cholesteryl acetate may be oxidized using RuCl3 and tBuOOH in CH2Cl2 to afford the enone containing compound 229. Exchange of the protecting group at C3 to the tBDMS derivative is followed by lithium ammonia reduction and trapping of the enolate anion with (MeO)2PCl giving the enol phosphate 231. A second lithium-ammonia reduction gives the xcex946,7 double bond which may be oxidized with OsO4 to afford compound 233 containing the 3xcex2,6xcex1,7xcex1-trihydroxylation pattern. 
More generally, compounds of the present invention may be characterized by the following formula: 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
C17 is substituted according to any of (c), (d), (e), (f), (g), (h) and (i):
(c) xe2x95x90C(R2)(R3) except when C14 is substituted with methyl;
(d) xe2x80x94R5 and xe2x80x94OR6 so long as the A and B rings are not aromatic, and when C10 is substituted with methyl then C5 is not bonded directly to oxygen, where R5 and R6 may together form a direct bond so C17 is a carbonyl group, or may together with C17 form a cyclic 3-6 membered ether or 4-6 membered lactone; otherwise R5 is R4or xe2x80x94OR6 and R6 is R1 or R4;
(e) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6, as long as one of the following conditions i), ii), iii) or iv) apply:
i) C5 is substituted with a hydrogen in the alpha configuation, and C3 is not bonded to oxygen, and when C3 is substituted with two hydrogen atoms then C17 is not substituted with either xe2x80x94CH(CH3)(CH2)3CH(CH3)2 or xe2x80x94CH(CH3)(CH2)2C(xe2x95x90O)OCH3;
ii) C10 and C13 are not simultaneously substituted with methyl, and when C10 is substituted with methyl, then C14 is not substituted with a methyl, and the A ring is never aromatic;
iii) if C3 and C4 are bonded to oxygen atoms, and the C6 xe2x80x94OR1 substituent has the alpha configuration, and the C7-OR1 substituent has the beta configuration, then C17 is not substituted with any of the following: 
iv) C3 and C4 are each bonded to the same oxygen atom so as to form an oxirane ring, with the proviso that C7 does not have carbonyl substitution when C5 has hydroxyl or xe2x80x94OR1 substitution;
(f) two of the following substituents, which are independently selected: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, as long as one of the above conditions i), ii), iii) or iv) apply;
(g) a cyclic structure of the formula 
wherein G is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OR1)xe2x80x94, xe2x80x94C(R4)(OR1)xe2x80x94 or xe2x80x94C(OR1)(OR1)xe2x80x94, as long as C3 and C4 are not simultaneously substituted with hydroxyl or protected hydroxyl;
(h) two hydrogen atoms, as long as C3 is not substituted with a carbonyl group;
(i) one hydrogen atom and one group selected from C1-C30 hydrocarbyl groups and C1-C30 halogen substituted hydrocarbyl groups, excluding xe2x80x94CH(CH3)(CH2)3CH(CH3)2;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R2, R3 and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R1 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In a preferred embodiment, the compounds of the invention have one of the structure set forth below, and mixtures thereof: 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C1, C2, C3, C4, C11, C12 and C16 is independently substituted according to (a) or (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6,
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
C5 is substituted with a hydrogen atom;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1, although C5 is preferably substituted with hydrogen; and
C17 is substituted according to (c), (d), (e) or (f):
(c) two substituents selected from hydrogen, halogen, C1-C30 saturated hydrocarbyl excluding xe2x80x94CH(CH3)(CH2)3CH(CH3)2, halogen substituted C1-C30 saturated hydrocarbyl, C1-C30 unsaturated hydrocarbyl, and halogen substituted C1-C30 unsaturated hydrocarbyl;
(d) one substituent selected from xe2x95x90C(R4)(R4) with the proviso that C14 is not substituted with methyl;
(e) at least one oxygen atom-containing substituent selected from xe2x95x90O, xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6, xe2x80x94OH, and xe2x80x94OR1;
(f) at least one nitrogen atom-containing substituent selected from xe2x80x94N(R4)(R4) wherein the two R4 groups may together with the nitrogen atom form one or more rings, so that the nitrogen atom-containing substituent includes nitrogen atom-containing heterocyclic groups; wherein
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated, however fully saturated rings are preferred;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where xe2x80x94OR1 groups bonded to adjacent carbon atoms may together form a cyclic structure which protects both hydroxyl groups;
R4 at each occurrence is independently selected from H and R5;
R5 is a C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R5 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide or iodide.
The compounds of general and preferred structures as disclosed herein may be prepared by synthetic methodology as set forth in the Schemes 1-54, the references cited herein and the Examples provided herein, as well as knowledge of the skilled artisan. The following are preferred synthetic procedures useful in preparing compounds of the present invention.
In one aspect, the invention provides a process for introducing an exocyclic olefin group to the C17 position of a 6,7-dioxygenated steroid. The process includes the step of providing a compound of Formula (10) (such a compounds may be commercially available or may be prepared by techniques disclosed herein), and then reacting the compound of Formula (10) with a Wittig reagent of Formula (11) in the presence of a base, to provide an olefin compound of Formula (12) 
Each of the compounds of Formulas (10) and (12) include pharmaceutically acceptable salts and solvates thereof. In Formula (10), (11) and (12):
each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
Ra, Rb and R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide, which is independently selected at each occurrence.
In preferred embodiments of the process, the base is selected from sodium t-butoxide, potassium t-butoxide and sodium hydride and the like. The base is preferably in admixture with an aprotic solvent. Suitable aprotic solvents include toluene, tetrahydrofuran, methylene chloride, dimethylformamide, dimethylsulfoxide, benzene and diethyl ether. In another preferred embodiment, Ra and Rb are independently selected from hydrogen and C1-C7 alkyl, and X is selected from chloride, bromide and iodide.
In another aspect, the invention provides a process for introducing 6xcex1,7xcex2-dioxygenation into a steroid. The process includes the steps of providing a steroid of Formula (13) having a carbonyl group at C7 and a double bond between C5 and C6. Steroids of Formula (13) may be prepared by, for example, synthetic methodology disclosed herein. In a subsequent step, the carbonyl group is reduced to a hydroxyl group, followed by a hydroboration of the double bond to provide a hydroxyl group at C6, wherein the C6 hydroxyl group has the xcex1-configuration and the C7 hydroxyl group has the xcex2-configuration, 
The compounds of Formulas (13) and (14) include pharmaceutically acceptable salts and solvates thereof. In Formula (13) and (14):
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In preferred embodiments of the process, the reduction is accomplished with sodium borohydride in combination with cerium(III) chloride heptahydrate. In another preferred embodiment of the process, the hydroboration is conducted with a hydroboration reagent selected from BH3 and 9-BBN, and preferably in the presence of an aprotic solvent. Suitable aprotic solvents include tetrahydrofuran, methylene chloride, diethyl ether, dimethyl sulfide and carbon disulfide. The hydroboration is preferably immediately followed by treatment with a peroxide, such as hydrogen peroxide or t-butylperoxide, and a base, such as sodium hydroxide and potassium hydroxide.
Another aspect of the invention provides a process for a stereocontrolled introduction of a hydroxyl group at C3 of a steroid nucleus. The process includes the step of providing a steroid compound of Formula (15) having a carbonyl group at C3. Steroid compounds of Formula (15) may be prepared by, for example, synthetic methods disclosed herein. This is followed by reducing the carbonyl group to a hydroxyl group with a reducing agent so as to provide at least one compound of Formulas (16) and (17) 
Each of the compounds of Formulas (15), (16) and (17) include pharmaceutically acceptable salts and solvates thereof. In the compounds of Formulas (15), (16) and (17):
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):
(a) one of: xe2x95x90O, xe2x95x90C(R4)(R4), xe2x80x94C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94 wherein n ranges from 1 to about 6;
(b) two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, each independently selected;
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of xe2x80x94X, xe2x80x94R4 or xe2x80x94OR1;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where vicinal xe2x80x94OR1 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal xe2x80x94OR1 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of xe2x80x94OR1 at C6 and C7 represents a carbonyl or protected carbonyl group;
R4 at each occurrence is independently selected from H and C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide and iodide.
In a preferred embodiment of this process, the reducing agent is selected from lithium trisiamylborohydride, lithium tri-sec-butylborohydride and potassium tri-sec-butylborohydride, and will predominantly provide the hydroxyl compound of Formula (16) (relative to the hydroxyl compound of Formula (17)). In another preferred embodiment, the reducing agent is selected from sodium borohydride and lithium aluminum hydride, and will predominantly provide the hydroxyl compound of Formula (17). In general, the inventive process will achieve a reduction of compounds of Formula (15) such that the product mixture contains a ratio of Formula (16) to Formula (17) compounds of other than 1:1.
As used herein, the term organic moiety of an indicated carbon number range refers to a stable arrangement of atoms composed of at least one and not more than about the maximum carbon number set forth in the range, typically not more than about 30 carbon atoms, and any number of non-carbon atoms.
The C1-30 organic moiety may be a saturated or unsaturated hydrocarbyl radical. A saturated hydrocarbyl radical is defined according to the present invention as any radical composed exclusively of carbon and hydrogen, where single bonds are exclusively used to join carbon atoms together. Thus, any stable arrangement of carbon and hydrogen atoms, having at least one carbon atom, is included within the scope of a saturated hydrocarbon radical according to the invention. Some specific terminology that may be used to refer to specific carbon atom arrangements will be discussed below.
The carbon atoms may form an alkyl group, i.e., an acyclic chain of carbon atoms which may be branched or unbranched (linear). Methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl are alkyl groups having 1 to 4 carbon atoms (commonly referred to as lower alkyl groups), and are exemplary of alkyl groups of the invention. The carbon atoms may form a cycloalkyl group, i.e., a cyclic arrangement of carbon atoms, where cyclopropyl, cyclobutyl, cyclopentyl are cycloalkyl groups of the invention having 3-5 carbon atoms. Additional groups within the scope of xe2x80x9ccycloalkylxe2x80x9d as defined herein are polycycloalkyl groups, defined below.
A polycycloalkyl group is an arrangement of carbon atoms wherein at least one carbon atom is a part of at least two separately identifiable rings. The polycycloalkyl group may contain bridging between two carbon atoms, where bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5,2.0]nonyl, tricycl[2.2.1.01]heptyl, norbornyl and pinanyl are representative examples. The polycycloalkyl group may contain one or more fused ring systems, where decalinyl (radical from decalin) and perhydroanthracenyl are representative examples. The polycycloalkyl group may contain a spiro union, in which a single atom is the only common member of two rings. Spiro[3.4]octyl, spiro[3.3]heptyl and spiro[4.5]decyl are representative examples.
In addition, the saturated hydrocarbyl radical can be composed of any combination of two or more of the above, i.e., any combination of alkyl and cycloalkyl groups. Thus, the R4 or R5 groups may be an alkyl group (e.g., methyl) with a cycloalkyl (e.g., cyclohexyl) substituent, so that R4 or R5 is a cyclohexylmethyl group. As another example, R4 or R5 may be a cycloalkyl group (e.g., cyclooctyl) having two alkyl substituents (e.g., a methyl and ethyl substituent), so that R4 or R5 is a methylethylcyclooctyl group. As a final example, R4 or R5 may be a cycloalkyl group with an alkyl substituent, where the alkyl substituent is substituted with a polycycloalkly substituent.
As indicated above, R4 or R5 may be an unsaturated hydrocarbyl radical. Such an R4 or R5 group is defined as having a carbon arrangement as set forth above for saturated hydrocarbyl radicals, with the additional feature that at least one bond between any two carbon atoms is other than a single bond. An alkyl group with a single double bond is referred to as an alkenyl group, while an alkyl group having more than one double bond is referred to as an alkapolyenyl group, where alkadienyl (2 double bonds) and alkatrienyl (3 double bonds) are exemplary. An alkyl group with a single triple bond is referred to as an alkynyl group, while an alkyl group having more than one triple bond is referred to as a alkapolyynyl group, where alkydiynyl (2 triple bonds) and alkatriynyl (3 triple bonds) are exemplary.
Likewise, the cycloalkyl group may have one or more double or triple bonds, and be included within the scope of an unsaturated hydrocarbyl radical according to the invention. Cycloalkenyl and cycloalkynyl are general names given to groups having a single carbon-based ring with a single double and triple bond in the ring, respectively. Cycloalkadienyl groups are cycloalkyl groups with two double bonds containedin the ring structure. The double bond may be exocyclic to the ring, e.g., a carbon atom of the ring may have a xe2x95x90CH2 group (i.e., a methylidene group) or higher homologue bonded to it.
A ring may be unsaturated to the extent of being aromatic, and still be included within the scope of an unsaturated hydrocarbyl radical. Thus, an aryl group, for example, phenyl and naphthyl, are included within the scope of such hydrocarbyl groups. As any combination of the above is also included within the scope of an unsaturated hydrocarbyl radical, aralkyl (R4 or R5 is an alkyl group with at least one aryl substituent, e.g., benzyl) and alkylaryl (R4 or R5 is an aryl ring with at least one alkyl substituent, e.g., tolyl) groups are included within the scope of R4 or R5. C6 aryls are a preferred component of organic moieties of the invention.
R4 or R5 includes organic moieties that contain a heteroatom. Heteroatoms according to the invention are any atom other than carbon and hydrogen. A preferred class of heteroatoms are naturally occurring atoms (other than carbon and hydrogen). Another preferred class are non-metallic (other than carbon and hydrogen). Another preferred class consists of boron, nitrogen, oxygen, silicon, phosphorous, sulfur, selenium and halogen (i.e., fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred). Another preferred class consists of nitrogen, oxygen, sulfur and halogen. Another preferred class consists of nitrogen, oxygen and sulfur. Oxygen is a preferred heteroatom. Nitrogen is a preferred heteroatom.
For example, R4 or R5 may be a hydrocarbyl radical as defined above, with at least one substituent containing at least one heteroatom. In this paragraph, R4 will be used to refer to both R4 and R5. In other words, R4 may be a hydrocarbyl radical as defined above, wherein at least one hydrogen atom is replaced with a heteroatom. For example, if the heteroatom is oxygen, the substituent may be a carbonyl group, i.e., two hydrogens on a single carbon atom are replaced by an oxygen, to form either a ketone or aldehyde group. Alternatively, one hydrogen may be replaced by an oxygen atom, in the form of an hydroxy, alkoxy, aryloxy, aralkyloxy, alkylaryloxy (where alkoxy, aryloxy, aralkyloxy, alkylaryloxy may be collectively referred to as hydrocarbyloxy), heteroaryloxy, xe2x80x94OC(O)R4, ketal, acetal, hemiketal, hemiacetal, epoxy and xe2x80x94OSO3M. The heteroatom may be a halogen. The heteroatom may be a nitrogen, where the nitrogen forms part of an amino (xe2x80x94NH2, xe2x80x94NHR4, xe2x80x94N(R4)2), alkylamido, arylamido, arylalkylamido, alkylarylamido, nitro, xe2x80x94N(R4)SO3M or aminocarbonylamide group. The heteroatom may be a sulfur, where the sulfur forms part of a thiol, thiocarbonyl, xe2x80x94SO3M, sulfonyl, sulfonamide or sulfonhydrazide group. The heteroatom may be part of a carbon-containing substituent such as formyl, cyano, xe2x80x94C(O)OR4, xe2x80x94C(O)OM, xe2x80x94C(O)R4, xe2x80x94C(O)N(R4)2, carbamate, carbhydrazide and carbohydroxamic acid.
In the above exemplary heteroatom-containing substituents, M represents proton or a metal ion. Preferred metal ions, in combination with a counterion, form physiologically tolerated salts. A preferred metal from which a metal ion may be formed include an alkali metal [for example, lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs)] an alkaline earth metal (for example, magnesium (Mg), calcium (Ca) and strontium (Sr)], or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). An alkali metal or an alkaline earth metal are preferred M groups. Sodium, potassium, magnesium and calcium are preferred M groups. Sodium and potassium are preferred M groups.
Another class of organic moieties according to the invention are hydrocarbyl radicals as defined above, wherein at least one carbon is substituted for at least one heteroatom. Examples of such organic moieties are heterocycloalkyl (a cycloalkyl group having at least one carbon replaced with at least one heteroatom), heterocycloalkenyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkenyl, etc. Collectively, this class of organic moieties may be referred to as heterohydrocarbyls. Another example of such organic moieties have a heteroatom bridging (a) the radical to which the organic moiety is bonded and (b) the remainder of the organic moiety. Examples include alkoxy, aryloxy, arylalkyloxy and alkylaryloxy radicals, which may collectively be referred to herein as hydrocarbyloxy radicals or moieties. Thus, xe2x80x94OR4 is an exemplary R4 group of the invention. Another example is xe2x80x94NHR4.
Examples of heterocycloalkylene are pyrrolidinylene, piperidinylene, tetrahydrofuranylene, di and tetrahydropyranylene. Examples of heterocycloalkyl are radicals derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine. Examples of heterocycloalkenyl substituents are radicals derived by removal of a hydrogen from 2- and 3-pyrroline, oxazoline, 2- and 4-imidazoline and 2- and 3-pyrazoline.
While the organic moiety may have up to about 30 carbon atoms, preferred organic moieties of the invention have fewer than 30 carbon atoms, for example, up to about 25 carbon atoms, more preferably up to about 20 carbon atoms. The organic moiety may have up to about 15 carbon atoms, or up to about 12 or 10 carbon atoms. A preferred category of organic moieties has up to about 8 or 6 carbon atoms.
The following are exemplary R4 and R5 organic moieties where R4 or R5 is joined to the steroid nucleus through a carbon atom: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, carboxylic acid, cyano and formyl.
The following are exemplary R4 and R5 organic moieties where R4 or R5 is joined to the steroid nucleus through an oxygen atom: hydroxy, oxo, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, aryloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloaikylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy and heterocyclyloxy.
R4 and R5 organic moieties may contain a nitrogen atom through which the R4 or R5 organic moiety is joined to the steroid nucleus. Examples are nitro and organic moieties of the formula xe2x80x94NL2L3 wherein L2 and L3 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, formyl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl and heterocyclylcarbonyl, such that L2 and L3 together may be alkylene or alkenylene to thereby form a 3- to 8-membered saturated or unsaturated ring in combination with the nitrogen atom to which they are attached.
The following are exemplary R4 and R5 organic moieties where the R4 or R5 moiety is joined to the steroid nucleus through a sulfur atom: alkylsulfide, alkenylsulfide, alkynylsulfide, cycloalkylsulfide, cycloalkenylsulfide, arylsulfide, heterocyclylsulfide, alkylcarbonylsulfide, alkenylcarbonylsulfide, alkynylcarbonylsulfide, cycloalkylcarbonylsulfide, cycloalkenylcarbonylsulfide, arylcarbonylsulfide, heterocyclylcarbonylsulfide, and groups of the formulas: xe2x80x94S(O)nH, xe2x80x94S(O)nL4, xe2x80x94S(O)mOH, xe2x80x94S(O)mOL4, xe2x80x94OS(O)mOL4, and xe2x80x94O(S)mOH, wherein L4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.
In the above R4 and R5 organic moieties, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups (collectively referred to as the R4 or R5 hydrocarbyl groups) may be fully or partially halogenated, and/or substituted with up to five L5 groups. The heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy groups (collectively referred to as the R4 heterocyclyl groups) may likewise be fully or partially halogenated and/or substituted with up to five L5 groups.
L5 groups contain a carbon, oxygen, nitrogen or sulfur atom through which they are joined to a carbon atom of the R4 or R5 hydrocarbyl groups or a carbon or nitrogen atom of the R4 or R5 heterocyclyl groups.
The following are exemplary L5 groups wherein a carbon atom of L5 is joined to the R4 hydrocarbyl or heterocyclyl group: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl and aryloxycarbonyl.
The following are exemplary L5 groups wherein an oxygen atom of L5 is joined to the R4 hydrocarbyl or heterocyclyl group: hydroxy, oxo, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, aryloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy and arylcarbonyloxy.
The L5 group may contain a nitrogen atom through which the L5 group is joined to the R4 or R5 hydrocarbyl or heterocyclyl group. Examples include nitro and nitrogen-containing groups of the formula xe2x80x94NL6L7 wherein L6 and L7 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl and arylcarbonyl such that L6 and L7 together may be alkylene or alkenylene to thereby form a 3- to 8-membered saturated or unsaturated ring in combination with the nitrogen atom to which they are attached.
The following are exemplary L5 groups wherein a sulfur atom of L5 is joined to the R4 or R5 hydrocarbyl or heterocyclyl group: alkylsulfide, alkenylsulfide, alkynylsulfide, cycloalkylsulfide, cycloalkenylsulfide, arylsulfide, alkylcarbonylsulfide, alkenylcarbonylsulfide, alkynylcarbonylsulfide, cycloalkylcarbonylsulfide, cycloalkenylcarbonylsulfide, arylcarbonylsulfide, and groups of the formulas: xe2x80x94S(O)nL8, xe2x80x94S(O)mOH, xe2x80x94S(O)mOL8, xe2x80x94OS(O)mOL8, and xe2x80x94O(S)mOH, wherein L8 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.
In the exemplary R4 and R5 organic moieties, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups which form part of L5 (collectively referred to as the L5 hydrocarbyl groups) may be fully or partially halogenated, and/or substituted with up to three L9 groups. The heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy groups (collectively referred to as the L5 heterocyclyl groups) may likewise be fully or partially halogenated, and/or substituted with up to three L9 groups.
L9 groups contain a carbon, oxygen, nitrogen or sulfur atom through which they are joined to the L5 hydrocarbyl group or the L5 heterocyclyl group.
The following are exemplary L9 groups wherein a carbon atom of L9 is joined to the L5 hydrocarbyl or heterocyclyl group: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl and heterocyclyloxycarbonyl.
The following are exemplary L9 groups wherein an oxygen atom of L9 is joined to the L5 hydrocarbyl or heterocyclyl group: hydroxy, oxo, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, aryloxy, heterocyclyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy and heterocyclylcarbonyloxy.
The L9 group may contain a nitrogen atom through which the L9 group is joined to the L5 hydrocarbyl or heterocyclyl group. Such nitrogen-containing L9 groups include nitro and groups having the formula xe2x80x94NL10L11 wherein L10 and L11 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl and heterocyclylcarbonyl such that L10 and L11 together may be alkylene or alkenylene to thereby form a 3- to 8-membered saturated or unsaturated ring in combination with the nitrogen atom to which they are attached.
The following are exemplary L9 groups wherein an sulfur atom of L9 is joined to the L5 hydrocarbyl or heterocyclyl group: alkylsulfide, alkenylsulfide, alkynylsulfide, cycloalkylsulfide, cycloalkenylsulfide, arylsulfide, heterocyclylsulfide alkylcarbonylsulfide, alkenylcarbonylsulfide, alkynylcarbonylsulfide, cycloalkylcarbonylsulfide, cycloalkenylcarbonylsulfide, arylcarbonylsulfide, heterocyclylcarbonylsulfide and groups of the formulas: xe2x80x94S(O)nL12, xe2x80x94S(O)mOH, xe2x80x94S(O)mOL12, xe2x80x94OS(O)mOL12, and xe2x80x94O(S)mOH, wherein L12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.
In the exemplary R4 and R5 organic moieties, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups which form part of L9 (collectively referred to as the L9 hydrocarbyl groups) may be fully or partially halogenated, and/or substituted with up to three L13 groups. The heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy groups (collectively referred to as the L9 heterocyclyl groups) may likewise be fully or partially halogenated, and/or substituted with up to three L13 groups.
An L13 group contains a carbon, oxygen, nitrogen or sulfur atom through which the L13 group is joined to the L9 hydrocarbyl group or L9 heterocyclyl group.
The following are exemplary L13 groups wherein a carbon atom of L13 is joined to the L9 hydrocarbyl or heterocyclyl group: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl and heterocyclyloxycarbonyl.
The following are exemplary L13 groups wherein an oxygen atom of L13 is joined to the L9 hydrocarbyl or heterocyclyl group: hydroxy, oxo, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, aryloxy, heterocyclyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy and heterocyclylcarbonyloxy.
The L13 group may contain a nitrogen atom through which the L13 group is joined to the L9 hydrocarbyl or heterocyclyl group. Such nitrogen-containing L13 groups include nitro and groups of the formula xe2x80x94NL14L15 wherein L14 and L15 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl and heterocyclylcarbonyl such that L15 and L15 together may be alkylene or alkenylene to thereby form a 3- to 8-membered saturated or unsaturated ring in combination with the nitrogen atom to which they are attached.
The following are exemplary L13 groups wherein an sulfur atom of L13 is joined to the L9 hydrocarbyl or heterocyclyl group: alkylsulfide, alkenylsulfide, alkynylsulfide, cycloalkylsulfide, cycloalkenylsulfide, arylsulfide, heterocyclylsulfide, alkylcarbonylsulfide, alkenylcarbonyisulfide, alkynylcarbonylsulfide, cycloalkylcarbonylsulfide, cycloalkenylcarbonylsulfide, arylcarbonylsulfide, heterocyclylcarbonylsulfide and groups of the formulas: xe2x80x94S(O)nL14, xe2x80x94S(O)mOH, xe2x80x94S(O)mOL14, xe2x80x94OS(O)mOL14, and xe2x80x94O(S)mOH, wherein L14 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.
In the groups set forth above, m is independently 1 or 2, and n is independently 0, 1 or 2.
Certain of the R4 and R5 substituents may contain asymmetric carbon atoms. Compounds containing such substituents may therefore exist in enantiomeric and diastereomeric forms and in racemic mixtures thereof. All are within the scope of the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
In accordance with the description of exemplary R4 or R5 organic moieties, the following terms have the designated meanings, unless explicitly stated otherwise:
Alkyl, alkenyl and alkynyl refer to straight or branched chain hydrocarbons having 1 to 30 carbon atoms (at least two carbon atoms for an alkynyl group) and no unsaturation, at least one double bond or at least one triple bond, respectively. Preferred carbon number ranges are 1 to 20 and 1 to 10.
Cycloalkyl and cycloalkenyl refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms, where a cycloalkyl group is saturated, and a cycloalkenyl group has at least one double bond within the cyclic structure. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl refers to refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
Carbocyclic aryl refers to aromatic groups wherein the ring atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include phenyl, naphthyl and indenyl groups.
Heterocyclic aryl refers to a mono- or bicyclic ring system of about 5 to about 12 carbon atoms, where each monocyclic ring may possess from 0 to about 4 heteroatoms, and each bicyclic ring may possess about 0 to about 5 heteroatoms selected from N, O, and S provided said heteroatoms are not vicinal oxygen and/or sulfur atoms. Examples of such mono- and bicyclic ring systems include, without limitation, benzofuran, benzothiophene, indole, benzopyrazole, coumarin, isoquinoline, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, triazole, quinoline, pyrimidine, pyridine, pyridone, pyrazine, pyridazine, isothiazole, isoxazole and tetrazole.
Biaryl refers to phenyl substituted by carbocyclic aryl or heterocyclic aryl as defined herein, ortho, meta or para to the point of attachment of the phenyl ring.
Heterocyclyl refers to a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to the steroid nucleus through any heteroatom or carbon atom of the heterocyclic ring which results in the creation of a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxcazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiarnorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
Heterocyclyloxy and heterocyclylcarbonyl refer to heterocyclyl groups bonded through an oxygen atom or a carbonyl group, respectively, to one of the to one or more of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Heterocyclyloxycarbonyl refers to a heterocyclyloxy group bonded through a carbonyl group to one or more of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Heterocyclylcarbonyloxy refers to a heterocyclylcarbonyl group bonded through an oxygen atom to one or more of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl and arylcarbonyl refer to moieties wherein a carbonyl group (Cxe2x95x90O) provides the carbon atom through which the moiety is joined to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group, and an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl group, respectively, is also joined to the carbonyl group.
Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl and aryloxycarbonyl refer to moieties wherein a carbonyl group (Cxe2x95x90O) provides the carbon atom through which the moiety is joined to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group, and an alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or aryloxy group, respectively, is also joined to the carbonyl group.
Alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy and aryloxy refer to groups wherein oxygen is bonded to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl group, respectively, and that oxygen is also bonded to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy and arylcarbonyloxy refer to groups wherein oxygen is bonded to an alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl and arylcarbonyl group, respectively, and that oxygen is also bonded to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Alkylsulfide, alkenylsulfide, alkynylsulfide, cycloalkylsulfide, cycloalkenylsulfide and arylsulfide refer to groups wherein sulfur is bonded to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl group, respectively, and that sulfur atom is also bonded to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Alkylcarbonylsulfide, alkenylcarbonylsulfide, alkynylcarbonylsulfide, cycloalkylcarbonylsulfide, cycloalkenylcarbonylsulfide and arylcarbonylsulfide refer to groups wherein a sulfur atom is bonded to a alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl or arylcarbonyl group, respectively, and that sulfur atom is also bonded to one of the steroid nucleus, R4 hydrocarbyl group, L5 hydrocarbyl group or L9 hydrocarbyl group.
Alkylene refers to a straight chain bridge of 1 to 5 carbon atoms, which may be substituted with 1 to 3 lower alkyl groups or fully or partially halogenated lower alkyl groups.
Alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds, which may be substituted with 1 to 3 lower alkyl groups or fully or partially halogenated lower alkyl groups.
Alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two triple bonds, which may be substituted with 1 to 3 lower alkyl group or fully or partially halogenated lower alkyl groups.
A lower alkyl group refers to C1-C5 alkyl groups, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, sec-butyl, iso-butyl, n-pentyl, iso-pentyl, etc.
Halogen refers to fluorine, chlorine, bromine and iodine, and a halogenated group refers to a carbon atom having at least one halogen bonded thereto.
Formyl refers to xe2x80x94C(xe2x95x90O)H; hydroxyl refers to xe2x80x94OH; and oxo refers to an oxygen atom which forms part of a carbonyl group.
A pharmaceutically acceptable salt includes acid addition salts and base addition salts.
Acid addition salts refer to those salts formed from steroid compounds of the invention and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and/or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
Base addition salts include those salts derived from steroids of the invention and inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
In another embodiment, the present invention provides compositions which include a 6,7-dioxygenated steroid compound as described above in admixture or otherwise in association with one or more inert carriers, as well as optional ingredients if desired. A pharmaceutical composition comprising a compound in combination with a pharmaceutically acceptable carrier or diluent, the compound having the formula 
including pharmaceutically acceptable salts and solvates thereof, wherein:
each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1;
each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted with a substituent selected from (a) or (b), wherein
(a) represents one of: xe2x95x90O, xe2x95x90C(R4)(R4), C(R4)(R4)(C(R4)(R4))nxe2x80x94 and xe2x80x94(O(C(R4)(R4))nO)xe2x80x94, wherein n ranges from 1 to about 6; and
(b) represents two of: xe2x80x94X, xe2x80x94R4 and xe2x80x94OR1, which are independently selected at each occurrence;
the A, B, C and D rings may independently be fully saturated, partially saturated or fully unsaturated;
R1 is H or a protecting group such that xe2x80x94OR1 is a protected hydroxyl group, where the C6 and C7-OR1 groups may together form a cyclic structure which protects both hydroxyl groups;
R4 at each occurrence is independently selected from H and R5;
R5 is a C1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur; where two geminal R4 groups may together form a ring with the carbon atom to which they are both bonded; and
X represents fluoride, chloride, bromide or iodide;
with the proviso that C15 is not bonded to an oxygen atom.
In preferred compositions: C17 is substituted with a hydrocarbyl group; such as a C1-C7 alkyl group; or such as an olefinic group of the formula xe2x95x90C(R4)(R4), where preferably R4 is hydrogen or C1-C10 alkyl; in a preferred embodiment the C17 hydrocarbyl group excludes xe2x80x94CH(CH3)(CH2)3CH(CH3)2. In other preferred compositions, C17 is substituted with two atoms independently selected from hydrogen and halogen atoms; or C17 is substituted with at least one oxygen atom; or C17 is substituted with a hydroxyl or protected hydroxyl group; or C17 is substituted with a carbonyl or protected carbonyl group; or C17 is substituted with an alkoxy group. In preferred compositions, the substituent at C17 excludes 
In other preferred composition, C15 is substituted with two hydrogen atoms; and/or C4 is substituted with hydrogen and one of xe2x80x94X, xe2x80x94R5 or xe2x80x94OR1; and/or C5 is substituted with hydrogen; and/or C4 is bonded to at least one hydrogen such that when C4 is bonded to two hydrogen atoms then C3 is not bonded to either oxygen or to two hydrogen atoms. In other preferred composition, C4 is bonded to two hydrogen atoms only when C3 is not bonded to either oxygen or to two hydrogen atoms. In another preferred composition, C4 is bonded to methyl only when C4 is not bonded to two methyls or formyl. In other preferred compositions, the compounds have a hydrogen at C5 in the alpha configuration. In another preferred composition, the compounds have an xe2x80x94OR1 group at C6 with the alpha configuration. In another preferred composition, the compounds have an xe2x80x94OR1 group at C7 with the beta configuration. In another preferred composition, the compounds have an xe2x80x94OR1 substituent at C6 with the alpha configuration and an xe2x80x94OR1 substituent at C7 with the beta configuration. In other preferred compositions, the compounds have at least one of C3 and C4 bonded to an oxygen atom, and in a preferred embodiment, both C3 and C4 are bonded to an oxygen atom. In another preferred composition, C10 of the compound is substituted with a methyl group; and/or C13 of the compound is substituted with a methyl group; or both C10 and C13 of the compounds are substituted with methyl groups. In a preferred composition, both C6 and C7 are bonded to hydrogen atoms. In another preferred composition, at least one of C1, C2, C3, C4, C5, C8, C9, C10, C11, C12, C13, C14, C15, C16 and C17 is substituted exclusively with hydrogen atoms, and more preferably C1 and C2 are substituted exclusively with hydrogen atoms; and/or C11 and C12 are substituted exclusively with hydrogen atoms; and/or C15 and C16 are substituted exclusively with hydrogen atoms. In a preferred composition, the compounds have a saturated A ring; and/or a saturated B ring; and/or a saturated C ring; and/or a saturated D ring. Compositions with compounds having a saturated A ring are preferred, and compositions with compounds having fully saturated A,B,C and D rings are more preferred. In another preferred composition, the A ring of the compound does not contain a bicyclic structure. In yet another preferred composition, C3 and C4 of the compound are not both substituted solely with hydrogen atoms. These compositions may be used for the treatment of asthma, allergy, inflammation including arthritis, and thrombosis. These compositions may also be formed into a medicament, which may used in the treatment of, for example, asthma, allergy, inflammation including arthritis, and thrombosis.
These compositions are useful as, for example, assay standards, convenient means of making bulk shipments, or pharmaceutical compositions. An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001 wt % to about 80 wt % of the entire weight of the composition. Inert carriers include any material which does not degrade or otherwise covalently react with a compound of the invention. Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers.
Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter, simply referred to as a pharmaceutical composition) containing a 6,7-dioxygenated steroid compound as described above, in admixture with a pharmaceutically acceptable carrier. The invention further provides a pharmaceutical composition containing an effective amount of a 6,7-dioxygenated steroid compound as described above, in association with a pharmaceutically acceptable carrier.
The pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of steroid in aerosol form may hold a plurality of dosage units.
Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.
In general, the pharmaceutical composition includes an active 6,7-dioxygenated steroid compounds as described herein, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
As a solid composition for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
The composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer""s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid composition intended for either parenteral or oral administration should contain an amount of the inventive compound such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the active steroid compound. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active compound.
The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 10% w/v (weight per unit volume).
The composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The composition may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.
The composition in solid or liquid form may include an agent which binds to the active steroid component(s) and thereby assists in the delivery of the active components. Suitable agents which may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
The pharmaceutical composition of the present invention may consist of gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, spacers and the like, which together may form a kit. Preferred aerosols may be determined by one skilled in the art, without undue experimentation.
Whether in solid, liquid or gaseous form, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in the treatment of asthma, allergy, inflammation (including arthritis) or thrombosis.
The pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art. Various steroid compounds are, and have been widely used as active ingredients in pharmaceutical composition intended for therapeutic use, and accordingly one of ordinary skill in the art is familiar with preparing such compositions. The steroid compounds of the present invention may be formulated into pharmaceutical compositions in a like manner.
A composition intended to be administered by injection can be prepared by combining the 6,7-dioxygenated steroid with water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the steroid so as to facilitate dissolution or homogeneous suspension of the steroid in the aqueous delivery system.
The compounds and compositions described above have utility in treating allergy and asthma, arthritis and/or thrombosis. The compounds and composition described above may also be used to treat a condition associated with an elevated level of NFxcexaB, wherein a subject in need thereof is administered an amount of the compound (or composition containing the compound) effective to lower the NFxcexaB activity. As used herein, xe2x80x9ctreating allergy and asthma, arthritis and/or thrombosisxe2x80x9d refers to both therapy for allergy and asthma, arthritis and thrombosis, and for the prevention of the development of the allergic response, bronchoconstriction, inflammation and the formation of blood clots that cause thrombosis and associated diseases. As also used herein, NF-kB activity refers to any increase or decrease in the transcriptional activity of genes that is attributable to, directly or indirectly, the binding of any members of the NF-kB family of proteins to all DNA sequences recognized by this family of proteins.
An effective amount of a compound or composition of the present invention is used to treat allergy, asthma, arthritis or thrombosis in a warm-blooded animal, such as a human. Methods of administering effective amounts of anti-allergy, anti-asthma, anti-arthritis and anti-thrombotic agents are well known in the art and include the administration of inhalation, oral or parenteral forms. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants and transdermal delivery systems; or inhalation dosage systems employing dry powder inhalers or pressurized multi-dose inhalation devices. Generally, oral or intravenous administration is preferred for the treatment of arthritis and thrombosis, while oral or inhalation/intranasal are preferred for asthma and allergy. The dosage amount and frequency are selected to create an effective level of the agent without harmful effects. It will generally range from a dosage of about 0.1 to 100 mg/kg/day, and typically from about 0.1 to 10 mg/Kg/day where administered orally or intravenously, for anti-allergy, anti-asthma, anti-arthritis or anti-thrombotic effects. Also, the dosage range will be typically from about 0.01 to 1 mg/Kg/day where administered intranasally or by inhalation for anti-asthma and anti-allergy effects.
Administration of compounds or compositions of the present invention may be carried out in combination with the administration of other agents. For example, it may be desired to administer a bronchodilator or a glucocorticoid agent for effects on asthma, a glucocorticoid for effects on arthritis, or an anti-histamine for effects on allergy. Non-steroid compounds may be co-administered with the steroids of the present invention, and/or non-steroid compounds may used in combination with the steroid compounds of the invention to provide a therapy for one or more of asthma, allergies, arthritis and thrombosis.
The following examples are offered by way of illustration and not by way of limitation.
Unless otherwise stated, flash chromatography and column chromatography may be accomplished using Merck silica gel 60 (230-400 mesh). Flash chromatography may be carried out according to the procedure set forth in: xe2x80x9cPurification of Laboratory Chemicalsxe2x80x9d, 3rd. edition, Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D. Perrin and W. L. F. Armarego, page 23. Column chromatography refers to the process whereby the flow rate of eluent through a packing material is determined by gravity. In all cases flash chromatography and radial chromatography may be used interchangeably. Radial chromatography is performed using silica gel on a Chromatotron Model #7924T (Harrison Research, Palo Alto, Calif.).
A typical work-up procedure for a reaction mixture involves dilution of the reaction mixture with an organic solvent (ethyl acetate or diethyl ether) and washing of the organic mixture with saturated sodium bicarbonate followed by saturated sodium chloride. The organic layer is then dried over MgSO4, the mixture is filtered and the filtrate evaporated to dryness in vacuo to yield the crude product which may or may not require further purification.
A typical work-up procedure for a Wittig reaction involves first quenching by the dropwise addition of water. The mixture is then diluted with ethyl acetate and washed with saturated sodium bicarbonate and then sodium chloride. The organic layer is dried over magnesium sulphate, filtered and evaporated to dryness.
A typical work-up procedure for a hydroboration reaction involves pouring the reaction mixture into saturated sodium chloride solution (200 ml) followed by extraction of the aqueous slurry with methylene chloride and then washing the combined organic layers with aqueous 25% sodium thiosulphate solution. The organic layer is then dried over magnesium sulphate, filtered and evaporated to dryness.
Reactions may typically be monitored with thin layer chromatography (TLC) using Silica gel 60 F254 plates (EM Science, Gibbstown, N.J.) and an appropriate solvent system. Thin layer chromatography may be carried out according to the procedure set forth in: xe2x80x9cPurification of Laboratory Chemicalsxe2x80x9d, 3rd. edition, Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D. Perrin and W. L. F. Armarego, page 30. After elution is complete, the TLC plate is dried, lightly sprayed with a 10% solution of H2SO4 in ethanol and then heated until the spots corresponding to the compounds appear. Unless otherwise stated, filtrations are carried out using a Whatman (type 1) filter paper.